Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity

ABSTRACT

Compounds of formula (I) described herein act both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists and are useful for the prevention and/or treatment of broncho-obstructive or inflammatory diseases.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.12195891.2 filed on Dec. 6, 2012, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds which act both as muscarinicreceptor antagonists and beta2 adrenergic receptor agonists. The presentinvention also relates to processes for preparing such a compound,compositions which contain such a compound, therapeutic uses of such acompound, and combinations of such a compound with other pharmaceuticalactive ingredients.

2. Discussion of the Background

Pulmonary disorders, such as asthma and chronic obstructive pulmonarydisease (COPD), are commonly treated with bronchodilators. A known classof bronchodilators consists of beta-2 adrenergic receptor agonists, suchas salbutamol, fenoterol, formoterol and salmeterol. These compounds aregenerally administered by inhalation.

Another known class of bronchodilators consists of muscarinic receptorantagonists (anticholinergic compounds), such as ipratropium andtiotropium. These compounds are also typically administered byinhalation.

Inhaled formulations of both beta-2 agonists and muscarinic receptorantagonists are valuable agents in the treatment of asthma and COPD,with both classes of agents providing symptomatic relief due to theirability to relax constricted airways. Observations that thebronchodilator effects of the two classes of agents were additive,prompted studies with combinations of the two agents. In 1975, it wasshown that beneficial effects could be achieved by combining twoingredients such as fenoterol and ipratropium bromide in a singleaerosol. This prompted the development of fixed dose combinations ofipratropium bromide firstly with fenoterol (Berodual, introduced in1980), and then with salbutamol (Combivent, introduced in 1994).

More recently the availability of both long-acting muscarinicantagonists and long-acting beta-2 agonists prompted to the developmentof combinations of these agents. For example, WO 00/69468 (which isincorporated herein by reference in its entirety) discloses medicamentcompositions containing a muscarinic receptor antagonist, such astiotropium bromide, and beta-2 adrenergic receptor agonists, such asformoterol fumarate or salmeterol, and WO 2005/115467 (which isincorporated herein by reference in its entirety) discloses acombination which comprises a beta-2 agonist and an antagonist of M3muscarinic receptors which is a salt of3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane.

An alternative approach to the development of fixed dose combinations isthe identification of molecules that combine both activities ofmuscarinic antagonism and beta-2 agonism. In fact compounds possessingboth beta-2 adrenergic receptor agonist and muscarinic receptorantagonist activity are highly desirable since such bifunctionalcompounds would provide bronchodilation through two independentmechanisms of action while having a single molecule pharmacokinetics.

Such kinds of compounds were described in some patent applications, suchas WO 2004/074246, WO 2004/074812, WO 2005/051946, WO 2006/023457, WO2006/023460, WO 2010/123766, WO 2011/048409 and co-pending patentapplication PCT/EP2012/060795 (all of which are incorporated herein byreference in their entireties).

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcompounds which act both as muscarinic receptor antagonists and beta2adrenergic receptor agonists.

It is another object of the present invention to provide novel methodsof preparing such a compound.

It is another object of the present invention to provide novelcompositions which contain such a compound.

It is another object of the present invention to provide novel methodsof treating and/or preventing certain diseases and conditions byadministering such a compound.

It is another object of the present invention to provide novel methodscombinations of such a compound with another active ingredient.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofcompounds of general formula I, described below, which act both asmuscarinic receptor antagonists and beta2 adrenergic receptor agonists.

It has now been found that some particular carbamate derivatives,besides possessing both beta-2 adrenergic receptor agonist andmuscarinic receptor antagonist activity, possess elevated affinity forthe M3 muscarinic receptors and long lasting bronchodilating activity.

In another embodiment, the present invention provides processes forpreparing such a compound.

In another embodiment, the present invention provides compositions whichcontain such a compound.

In another embodiment, the present invention provides methods ofpreventing and/or treating certain diseases and conditions byadministering such a compound.

In another embodiment, the present invention provides combinations ofsuch a compound with other pharmaceutical active ingredients among whichare, for instance, those currently used in the treatment of respiratorydisorders, among which beta2-agonists, antimuscarinic agents,mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclearfactor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophilelastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors,leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs),antitussive agents, mucus regulators, mucolytics,expectorant/mucokinetic modulators, peptide mucolytics, antibiotics,inhibitors of JAK, SYK inhibitors, inhibitors of PI3Kdelta or PI3Kgamma,corticosteroids, and M3-antagonists/PDE4-inhibitors (MAPI).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In particular, the invention is directed to compounds of general formulaI:

wherein

Q is a group of formula Q1, Q2, or Q3

Z is H or OH;

Y is Y′ or Y1 which are divalent groups of formula

wherein

A1 and A2 are independently absent or (C₁-C₆)alkylene;

B is absent or is selected from the group consisting of arylene andheteroarylene, optionally substituted by one or more groups selectedfrom halogen, (C₁-C₆)alkyl, halo (C₁-C₆)alkyl, and (C₁-C₆)alkoxy;

C is absent or is —OC(O)— or is one of the following groups C1-C3

wherein R₄ is H or linear or branched (C₁-C₄)alkyl;

D is absent or is selected from the group consisting of arylene andheteroarylene, optionally substituted by one or more (C₁-C₆)alkylgroups;

n and n′ are independently 0 or an integer from 1 to 3;

E is absent or is selected from —O— and —OC(O)—;

G is arylene;

R₁ and R₂ are independently H or aryl;

R₃ is a group of formula J1 or J2

wherein R₅ is a group of formula K

wherein p′ is 0 or 1, P is absent or is CO, q is absent or is 1 and W isheteroaryl; and pharmaceutically acceptable salts and solvates thereof.

The expression “(C₁-C_(x))alkyl” refers to straight or branched chainalkyl groups wherein the number of carbon atoms is from 1 to x. Examplesof groups are methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl,hexyl, and the like.

The expression “halo(C₁-C₆)alkyl” refers to straight or branched chainalkyl groups wherein the number of carbon atoms is from 1 to 6,substituted by one or more halogen atoms.

In an analogous manner, the expression “(C₁-C_(x))alkylene” refers todivalent groups, such as methylene, ethylene, n-propylene, isopropylene,t-butylene, pentylene, hexylene, octylene, nonylene, decylene,undecylene, dodecylene and the like.

The expression “(C₁-C₁₀)alkoxy” refers to alkyl-oxy (e.g. alkoxy)groups, being the alkyl portion as above defined. Examples of saidgroups comprise methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like.

The expression “aryl” refers to mono, bi- or tricyclic ring systemshaving 5 to 20, preferably from 5 to 15, ring atoms, and wherein atleast one ring is aromatic.

The expression “heteroaryl” refers to mono, bi- or tri-cyclic systemswith 5 to 20 ring atoms, preferably from 5 to 15, in which at least onering is aromatic and in which at least one carbon ring atom is aheteroatom or heteroaromatic group (e.g. N, NH, S or O).

Examples of suitable aryl or heteroaryl monocyclic systems include, forinstance, thiophene (thiophenyl), benzene (phenyl), pyrrole (pyrrolyl),pyrazole (pyrazolyl), imidazole (imidazolyl), isoxazole (isoxazolyl),oxazole (oxazolyl), isothiazole (isothiazolyl), thiazole (thiazolyl),pyridine (pyridinyl), imidazolidine (imidazolidinyl), furan (furanyl)radicals and the like.

Examples of suitable aryl or heteroaryl bicyclic systems includenaphthalene (naphthyl), biphenylene (biphenylenyl), purine (purinyl),pteridine (pteridinyl), benzotriazole (benzotriazolyl), quinoline(quinolinyl), isoquinoline (isoquinolinyl), indole (indolyl), isoindole(isoindolyl), benzothiophene (benzothiophenyl), dihydrobenzo dioxin,dihydro-indene, dihydrobenzo dioxepin, benzo oxazin radicals and thelike.

Examples of suitable aryl or heteroaryl tricyclic systems includefluorene radicals as well as benzocondensed derivatives of theaforementioned heteroaryl bicyclic systems.

In an analogous manner, the expressions “arylene” and “heteroarylene”refer to divalent groups, such a phenylene, biphenylene and thienylene.

Whenever basic amino or quaternary ammonium groups are present in thecompounds of formula I, physiological acceptable anions, selected amongchloride, bromide, iodide, trifluoroacetate, formate, sulfate,phosphate, methanesulfonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate,pamoate and naphthalene disulfonate may be present. Likewise, in thepresence of acidic groups such as COOH groups, correspondingphysiological cation salts may be present as well, for instanceincluding alkaline or alkaline earth metal ions.

It will be apparent that the compounds of general formula I may containasymmetric centers. Therefore, the invention also includes any of theoptical stereoisomers, diastereoisomers and mixtures thereof, in anyproportion.

In particular, the carbon atom linked to R₁, R₂, G and —NH— groups,depending on the meanings provided to R₁ and R₂ among those formerlyreported, may represent a chiral center.

In an embodiment, the configuration is (S).

In another embodiment, the absolute configuration of this chiral centeris preferably (R).

In another preferred embodiment, the compounds of general formula Idescribed in the present invention are present as mixtures ofdiastereoisomers.

It is apparent to those skilled in the art that compounds of generalformula I wherein R₃ is J1 or J2

may contain three stereogenic centers, as indicated below with anasterisk (*).

This means that the structure of formula I is characterized by eightdifferent stereoisomers.

It is to be understood that all preferred groups or embodimentsdescribed herebelow for compounds of formula I may be combined amongeach other and apply as well mutatis mutandis.

A first preferred group of compounds is that of general formula Iwherein Q is a group of formula Q1, Q2 or Q3

Z is H or OH; Y is Y′ or Y1 which are divalent groups of formula

wherein A1 and A2 are independently absent or (C₁-C₆)alkylene; B isabsent or is selected from the group consisting of arylene andheteroarylene, optionally substituted by one or more groups selectedfrom halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy; C isabsent or is —OC(O)— or is one of the following groups C1-C3

wherein R₄ is H or linear or branched (C₁-C₄)alkyl; D is absent or isselected from the group consisting of arylene and heteroarylene,optionally substituted by one or more (C₁-C₆)alkyl groups; n and n′ areindependently 0 or an integer from 1 to 3; E is absent or is selectedfrom —O— and —OC(O)—; G is arylene; R₁, R₂ and R₃ are as defined above.

Still more preferred within this first group, are the compounds ofgeneral formula I, wherein Q is Q1

Z is —OH, Y is Y′ which is a divalent group of formula

A1 and A2 are independently absent or (C₁-C₆)alkylene; B is absent or isselected from the group consisting of arylene and heteroarylene,optionally substituted by one or more groups selected from halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy; C is absent or is—OC(O)— or is one of the following groups C1-C3

wherein R₄ is H or linear or branched (C₁-C₄)alkyl; D is absent or isarylene, optionally substituted by one or more (C₁-C₆)alkyl groups; nand n′ are independently 0 or an integer from 1 to 3; E is absent or is—O—; and G is arylene.

Still more preferred within this first group, are the compounds ofgeneral formula I, wherein A1 is selected from the group consisting ofmethylene, ethylene, and propylene; A2 is absent or is selected from thegroup consisting of methylene, ethylene, and propylene; B is absent oris selected from the group consisting of phenylene, naphthalene,pyridinediyl, furanediyl, thiophenediyl, and pyrazolediyl; C is absentor is —OC(O)— or is a group of formula C2

wherein n is 2; n′ is 1; D is absent or is phenylene; E is absent or is—O— and G is phenylene.

A second group of preferred compounds of general formula I, is thatwherein Q is Q1

Z is —OH, Y is Y1 which is a divalent group of formula

A1 is absent or (C₁-C₆)alkylene; C is absent or is —OC(O)— or is C1

wherein R₄ is H; B is absent or is selected from the group consisting ofarylene and heteroarylene, optionally substituted by one or more groupsselected from halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, and(C₁-C₆)alkoxy; D is absent or is arylene; n′ is 0 or an integer from 1to 3; E is absent or is —O—; and G is arylene.

Still more preferred within this class, are the compounds of generalformula I, wherein A1 is butylene, C is absent or is —OC(O)— or is C1

wherein R₄ is H; B is absent or is selected from the group consisting ofpyrazolediyl, thiophenediyl, pyridinediyl, furanediyl, and oxazolendiyl,optionally substituted by one or more groups selected from methyl; D isabsent; n′ is 1; E is —O—; G is phenylene and R₃ is a group of formulaJ1 or J2

wherein R₅ is a group of formula K

wherein p′ is 0 or 1, P is absent or is CO, q is absent or is 1, and Wis heteroaryl; and pharmaceutically acceptable salts and solvatesthereof.

The present invention also provides pharmaceutical compositions ofcompounds of formula I alone or in combination with or in admixture withone or more pharmaceutically acceptable carriers and/or excipients.

The present invention also provides the use of compounds of formula Ifor preparing a medicament.

In a further aspect, the invention provides the use of compounds offormula I for the prevention and/or treatment of any broncho-obstructiveor inflammatory disease, preferably asthma or chronic bronchitis orchronic obstructive pulmonary disease (COPD).

In a further aspect, the invention provides the use of compounds offormula I for the manufacture of a medicament for the prevention and/ortreatment of any broncho-obstructive or inflammatory disease, preferablyasthma or chronic bronchitis or chronic obstructive pulmonary disease(COPD).

The present invention further provides a method for prevention and/ortreatment of any broncho-obstructive or inflammatory disease, preferablyasthma or chronic bronchitis or chronic obstructive pulmonary disease(COPD), which comprises administering to a subject in need thereof atherapeutically effective amount of a compound of general formula I.

The present invention also provides pharmaceutical compositions suitablefor administration by inhalation.

Inhalable preparations include inhalable powders, propellant-containingmetering aerosols or propellant-free inhalable formulations.

The present invention also provides a device which may be a single- ormulti-dose dry powder inhaler, a metered dose inhaler and a soft mistnebulizer comprising the compounds of formula I.

The present invention is also directed to a kit comprising thepharmaceutical compositions of compounds of formula I alone or incombination with or in admixture with one or more pharmaceuticallyacceptable carriers and/or excipients and a device which may be asingle- or multi-dose dry powder inhaler, a metered dose inhaler and asoft mist nebulizer comprising the compounds of general formula I.

According to specific embodiments, the present invention provides thecompounds reported below:

Cpd Chemical Name 12-(4-((((R)-2-Hy1droxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methylphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 22-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 32-(2-Chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 42-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxyphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 52-(2-Bromo-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 62-(2-Chloro-3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 72-((4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)15aphthalene-1-yl)oxy)ethyl4-((3-((S)-phenyl((( ®-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 82-(3-Chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 92-(3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 102-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2,6-dimethylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 112-(2-Chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-6-methoxyphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 122-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxyphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 132-(2-Bromo-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 142-(2,6-Dichloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate 152-(2-Fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 162-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2,6-dimethoxyphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)benzoate 172-(2-Chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 184-(2-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzyl 3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 192-Fluoro-4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzyl 4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 204-(2-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)-3-methoxybenzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 213-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzyl 3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 223-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 23(6-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)pyridin-3-yl)methyl 4-((3-(S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 24(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)furan-2-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 252-Fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 265-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 27(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)furan-2-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 28(5-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)thiophen-2-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 29(5-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)thiophen-3-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 303-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl 3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 314-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 31A(5-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)thiazol-2-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 31B(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)isoxazol-3-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 31C(5-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-1-methyl-1H-pyrazol-3-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)benzoate 323-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)propyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 334-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 34(1-(3-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)-1H-pyrazol-4-yl)methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 352-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-1H-pyrazol-1-yl)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate 364-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl 1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylate 374-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)thiophene-2-carboxylate 384-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl 5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)nicotinate 39(R)-Quinuclidin-3-yl ((S)-(3-((3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate 39A(R)-Quinuclidin-3-yl((S)-(3-((3-(ethyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate 39B(R)-Quinuclidin-3-yl((S)-(3-((3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate 39C(R)-Quinuclidin-3-yl((S)-(3-((3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzyl)-carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)-methyl)carbamate 39D (R)-quinuclidin-3-yl((S)-(3-((3-((3-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate 40(R)-Quinuclidin-3-yl ((S)-(3-((5-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)furan-2-yl)methoxy)phenyl)(phenyl)methyl)carbamate 40A (R)-Quinuclidin-3-yl((S)-(3-((5-(ethyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)furan-2-yl)methoxy)phenyl)(phenyl)methyl)carbamate 41 (R)-Quinuclidin-3-yl((S)-(3-((4-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)oxazol-2-yl)methoxy)phenyl)(phenyl)methyl)carbamate 41A (R)-Quinuclidin-3-yl((S)-(3-((4-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)thiazol-2-yl)methoxy)phenyl)(phenyl)methyl)carbamate 41B (R)-Quinuclidin-3-yl((S)-(3-((3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)benzyl)oxy)-phenyl)(phenyl)methyl)carbamate 41C (R)-Quinuclidin-3-yl((S)-(3-((5-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)furan-3-yl)methoxy)phenyl)(phenyl)methyl)carbamate 42(R)-3-((S)-(3-((5-((4-((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)butoxy)carbonyl)furan-2-yl)methoxy)phenyl)(phenyl)methylcarbamoyloxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride hydrochloride 43(R)-Quinuclidin-3-yl((S)-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)-benzyl)oxy)phenyl)(phenyl)methyl)carbamate 44 (R)-Quinuclidin-3-yl((S)-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzyl)carbamoyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate 45(R)-Quinuclidin-3-yl ((S)-(3-((5-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)carbamoyl)-1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)(phenyl)methyl)carbamate 46(R)-Quinuclidin-3-yl ((S)-(3-((5-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)carbamoyl)-1-ethyl-1H-pyrazol-3-yl)methoxy)phenyl)(phenyl)methyl)carbamate 47(R)-Quinuclidin-3-yl ((S)-(3-((4-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)(methyl)carbamoyl)benzyl)-oxy)phenyl)(phenyl)methyl)carbamate 48 (R)-Quinuclidin-3-yl((S)-(3-((4-(ethyl(4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)benzyl)-oxy)phenyl)(phenyl)methyl)carbamate 49 (R)-Quinuclidin-3-yl((S)-(3-((3-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)carbamoyl)-benzyl)oxy)phenyl)(phenyl)methyl)carbamate 50 (R)-Quinuclidin-3-yl((S)-(3-((3-(ethyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)-phenyl)(phenyl)methyl)carbamate 51 (R)-Quinuclidin-3-yl((S)-(3-((4-(2-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)amino)-2-oxoethyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate 52(R)-Quinuclidin-3-yl((S)-(3-((4-(2-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)amino)-2-oxoethyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate 53(R)-Quinuclidin-3-yl((S)-(3-((5′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)(phenyl)methyl)carbamate 54 (R)-Quinuclidin-3-yl((S)-(3-((4′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)(phenyl)methyl)carbamate 55 (R)-Quinuclidin-3-yl((S)-(3-((3′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-4′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)(phenyl)methyl)carbamate 56 (R)-Quinuclidin-3-yl((S)-(3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate 57 (R)-Quinuclidin-3-yl((S)-(3-((5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)furan-2-yl)methoxy)phenyl)-(phenyl)methyl)carbamate 58 (R)-Quinuclidin-3-yl((S)-(3-((3-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate 59 (R)-quinuclidin-3-yl((S)-(3-((3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate 60 (R)-Quinuclidin-3-yl((S)-(3-((6-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)pyridin-3-yl)methoxy)phenyl)-(phenyl)methyl)carbamate 61 (R)-Quinuclidin-3-yl((S)-(3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzyl)oxy)-phenyl)(phenyl)methyl)carbamate 62 (R)-Quinuclidin-3-yl((S)-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate 63 (R)-Quinuclidin-3-yl((S)-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxyphenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate 64 (R)-Quinuclidin-3-yl((S)-(3-(2-((2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate 65(R)-Quinuclidin-3-yl((S)-(3-(2-((3-ethoxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate 66 (R)-Quinuclidin-3-yl((S)-(3-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)-3-(trifluoromethyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate 67(R)-quinuclidin-3-yl((S)-(3-((3-chloro-4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate 68 (R)-quinuclidin-3-yl((S)-(3-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)-2-methylbenzyl)oxy)phenyl)-(phenyl)methyl)carbamate

The present invention also provides pharmaceutical compositionscomprising a compound of the invention, either as such or aspharmaceutically acceptable salt, and one or more pharmaceuticallyacceptable carriers and/or excipients.

The compounds of the invention may be administered as the sole activeagent or in combination with other pharmaceutical active ingredientsincluding those currently used in the treatment of respiratorydisorders, e.g. beta2-agonists, antimuscarinic agents, mitogen-activatedprotein kinases (P38 MAP kinase) inhibitors, nuclear factor kappa-Bkinase subunit beta (IKK2) inhibitors, human neutrophil elastase (HNE)inhibitors, phosphodiesterase 4 (PDE4) inhibitors, leukotrienemodulators, non-steroidal anti-inflammatory agents (NSAIDs), antitussiveagents, mucus regulators, mucolytics, expectorant/mucokineticmodulators, peptide mucolytics, antibiotics, inhibitors of JAK, SYKinhibitors, inhibitors of PI3Kdelta or PI3Kgamma, corticosteroids, andM3-antagonists/PDE4-inhibitors (MAPI).

The present invention also provides combinations of a compound of theinvention, either as such or as pharmaceutically acceptable salt, with aβ2-agonist selected from the group consisting of carmoterol, GSK-642444,indacaterol, milveterol, arformoterol, arformoterol tartrate,formoterol, formoterol fumarate, salmeterol, salmeterol xinafoate,salbutamol, albuterol, levalbuterol, terbutaline, indacaterol (QAB-149),AZD-3199, BI-1744-CL, LAS-100977, GSK159797, GSK59790, GSK159802,GSK642444, GSK678007, GSK96108, bambuterol, isoproterenol, procaterol,clenbuterol, reproterol, fenoterol, bitolterol, brodxatelor, andASF-1020 and salts thereof.

The present invention also provides combinations of a compound of theinvention, either as such or as pharmaceutically acceptable salt, withan antimuscarinic agent selected from the group consisting ofaclidinium, tiotropium, tiotropium bromide (Spiriva®), ipratropium,ipratropium bromide, trospium, glycopyrrolate, NVA237, LAS34273,GSK656398, GSK233705, GSK57319, LAS35201, QAT370 and oxitropium salts.

The present invention also provides combinations of a compound of theinvention, either as such or as pharmaceutically acceptable salt, with aPDE4 inhibitor selected from the group consisting of AN-2728, AN-2898,CBS-3595, apremilast, ELB-353, KF-66490, K-34, LAS-37779, IBFB-211913,AWD-12-281, cipamfylline, cilomilast, roflumilast, BAY19-8004 andSCH-351591, AN-6415, indus-82010, TPI-PD3, ELB-353, CC-11050,GSK-256066, oglemilast, OX-914, tetomilast, MEM-1414, and RPL-554.

The present invention also provides combinations of a compound of theinvention, either as such or as pharmaceutically acceptable salt, with aP38 MAP kinase inhibitor selected from the group consisting ofsemapimod, talmapimod, pirfenidone, PH-797804, GSK-725, GSK856553,GSK681323, minokine, and losmapimod and salts thereof.

In a preferred embodiment, the present invention provides combinationsof a compound of the invention with an IKK2 inhibitor.

The invention also provides combinations of a compound of the inventionwith a HNE inhibitor selected from the group consisting of AAT,ADC-7828, aeriva, TAPI, AE-3763, KRP-109, AX-9657, POL-6014, AER-002,AGTC-0106, respriva, AZD-9668, zemaira, AAT IV, PGX-100, elafin,SPHD-400, prolastin C and prolastin inhaled.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with aleukotriene modulator selected from the group consisting of montelukast,zafirlukast, and pranlukast.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with a NSAIDselected from the group consisting of ibuprofen and ketoprofen.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with anantitussive agent, selected from the group consisting of codeine anddextramorphan.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with a mucolytic,selected from the group consisting of N acetyl cysteine and fudostein.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with anexpectorant/mucokinetic modulator, selected from the group consisting ofambroxol, hypertonic solutions (e.g. saline or mannitol) and surfactant.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with a peptidemucolytic, selected from the group consisting of recombinant humandeoxyribonuclease I (dornase-alfa and rhDNase) and helicidin.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with anantibiotic, selected from the group consisting of azithromycin,tobramycin, and aztreonam.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with a mucusregulator selected from the group consisting of INS-37217, diquafosol,sibenadet, CS-003, talnetant, DNK-333, MSI-1956, and gefitinib.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with an inhibitorof JAK, selected from the group consisting of CP-690550 and GLPG0634.

The invention also provides combinations of a compound of the invention,either as such or as pharmaceutically acceptable salt, with a SYKinhibitor selected from the group consisting of R406, R343, andPRT062607.

The invention also provides combinations of a compound of formula (I)with a corticosteroid selected from the group consisting ofdexamethasone, fluticasone, fluticasone furoate, fluticasone propionate,prednisolone, betamethasone, budesonide, mometasone, mometasone furoate,triamcinolone acetonide, ciclesonide, TPI-1020, beclomethasone,beclomethasone dipropionate, prednisone, deflazacort, hydrocortisone,QAE-397, and flunisolide.

The compounds of the invention can be prepared from readily availablestarting materials using the following general methods and procedures orby using other information readily available to those of ordinary skillin the art. Although a particular embodiment of the present inventionmay be shown or described herein, those skilled in the art willrecognize that all embodiments or aspects of the present invention canbe prepared using the methods described herein or by using othermethods, reagents and starting materials known to those skilled in theart. It will also be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. While the optimumreaction conditions may vary depending on the particular reactants orsolvent used, such conditions can be readily determined by one skilledin the art by routine optimisation procedures.

Compounds of general formula I may be prepared according to thefollowing synthetic Schemes 1 and 2.

General Procedure for the Preparation of Compounds of Formula I

The compounds of general formula VIII represent a compound wherein A1 isalkylene substituted with oxo, leading to an aldehyde or ketoneprotected as cyclic acetal. The cyclic acetal protecting group (PG) canbe removed leading to a compound of general formula XXIII.

The synthesis of compounds of general formula I may require theprotection of potential reactive functionality in addition to thosemethods already described. In such a case, examples of compatibleprotecting groups (PG) and their particular methods of protection anddeprotection are described in “Protecting groups in organic Synthesis”by T. W. Green and P. Wutz (Wiley-Interscience publication, 1999), whichis incorporated herein by reference in its entirety. Compounds ofgeneral formula I can be prepared for example by reaction of a compoundof general formula XVII with a compound of general formula XVIII. Thisreductive amination reaction can be performed following severaldifferent protocols described in the literature and known for theskilled in the art. For example, it can be performed in solvent such asmethanol, ethanol, tetrahydrofuran (THF) or dichloromethane (DCM) usinga reducing agent such as NaBH₄, NaCNBH₃ or NaBAcO₃H. It could be usefulto obtain the imine before adding the reducing agent. The reactionproceeds smoothly at RT over 1 to 12 hours.

The intermediate of general formula XVII can be easily prepared byreaction of a compound of general formula XIII with a compound ofgeneral formula XV. The reaction occurs smoothly at RT or lowertemperature in a solvent such as DCM or pyridine over 1-16 hours leadingto compounds of formula XVI that can be easily deprotected in aqueousacidic solution, leading to a compound of general formula XVII (seeScheme 1).

Compounds of general formula XV are either commercially available or canbe prepared by reacting an alcohol of general formula XIV with forexample diphosgene in a solvent such as DCM, THF or acetonitrile (ACN)at RT or lower temperature, over a period of time ranging from 0.5 to 12hours, leading to a compound of general formula XV wherein the leavinggroup LG is chlorine. Alternatively alcohol of general formula XIV canbe reacted with for example carbonyldiimidazole (CDI) leading to thesame intermediate wherein LG is imidazole. Other possible intermediateswith other known LGs can be prepared as described in the literature.

Compound of general formula XIII may be prepared from a compound ofgeneral formula XI via Ritter reaction (acetonitrile and sulfuric acidat RT) followed by hydrolysis of the intermediate acetamide performedunder basic condition.

Alternatively compounds of general formula XIII can be prepared byreduction of azide formula XII via hydrogenation under hydrogenatmosphere or hydrogen transfer conditions. The reaction occurs inalcohols at RT or higher temperature and stops in 1 to 12 hours. Analternative reduction method could be the Staudinger reaction, whichinvolves treatment of the azide, first with for exampletriphenylphosphine, followed by hydrolysis of the iminophosphoraneintermediate with water. This reaction occurs at RT in a water misciblesolvent such as for example THF. The use of a strong reducing agent suchas for example LiAlH₄ in THF or ether at −40° C. or lower temperaturecould easily allow to perform the required conversion of compound XIVinto XIII.

Azide XII is obtained from compound of formula XI by reaction withdiphenyl phosphoryl azide. The reaction is performed in a high boilingpoint such as toluene or xylene in the presence of a strong base suchas, but not limited to 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at atemperature ranging from 80 to 120° C. and it completes over 12 to 24hours. Alternatively the hydroxyl moiety of intermediate of formula XIcan be converted into a suitable leaving group (LG), such as for examplemesyl, tosyl or halogen and then reacted with an alkaline azide in apolar solvent such as acetonitrile, DMF or N-Methyl-2-pyrrolidone (NMP)at RT or higher temperature.

Intermediates of general formula XI can be prepared in several differentways. For example they can be prepared from reaction of a compound ofgeneral formula VII, wherein E is —O—, and an aldehyde of generalformula V featuring a suitable hydroxyl group that can convenientlyreact under standard Mitsunobu conditions. The reaction is done insolvents such as THF or N-methyl-morpholine (NMM) at a temperature from−10° C. to RT and completes in 1 to 24 hours. It occurs in the presenceof diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate(DIAD) and an organic phosphine such as, but not limited to,triphenylphosphine.

Alcohol of general formula VII is either commercially available or itcan be prepared from compound of formula II by addition of a Grignardreagent of formula VI. The reaction is normally done in an aproticsolvent such as ether or THF at RT or lower temperature and completesover 0.5 to 12 hours. Alternatively it can be prepared by reduction of acompound of general formula II, wherein R₂ is not hydrogen, with areducing agent such as, but not limited to, NaBH₄, leading in this caseto a compound of formula VII wherein R₁ is hydrogen. The reaction isperformed in a solvent such as methanol, ethanol or THF and completesover a period of time ranging from 1 to 12 hours. A similar syntheticprotocol can be used for the preparation of intermediate XI fromcompounds of general formula IV.

It is clear to a person skilled in the art that the preparation ofcompound of general formula VII or XI can be accomplished via inverseGrignard reaction in which Grignard of formula G-MgBr react with acompound of formula R₁C(O)R₂ under the same reaction conditionsdescribed above.

Compounds of general formula IV wherein E is —O—, can be prepared from acompound of general formula II, following an approach similar to thatdescribed for the preparation of compounds of formula XI from VII.Alternatively the compounds of general formula IV can be obtained byalkylation of a compound of general formula II, with a compound ofgeneral formula III wherein LG is a suitable leaving group such astosylate, mesylate or halogen. The reaction is normally done in polarsolvents such as acetonitrile or DMF, occurs in a presence of a basesuch as for example alkaline carbonate, bicarbonates or organic basesand completes over a period of time varying from 1 to 24 hours.

Preparation of compounds of formula X can be achieved by reaction of acompound of general formula IX, or the analogue wherein the bromine issubstituted by iodine or triflate, with a compound of general formulaVIII, wherein n is 2, under transition metal catalyzed cross-couplingreaction conditions. The terminal alkene VIII can be reacted under forexample the heck reaction condition with IX, leading to an alkenyleneintermediate X that can be easily reduced by mean of a classicalcatalytic hydrogenation of double bond to give compounds of formula IV.A great number of protocols, reagents and catalysts can be convenientlyused to achieve the desired conversion, as it is known to a personskilled in the art.

Alternatively, compounds of general formula I featuring an ester moietyin the linker Y, can be prepared by treating a compound of generalformula XXXVI with a compound of general formula XXXVII, wherein A2 isfunctionalized with OH, under the condensation reaction condition forthe preparation of esters. It is possible prepare a compound of generalformula I, wherein C is equal to C1, reacting a compound of generalformula XXXVI with a compound XXXVII wherein A2 is substituted with —NR₄under the known reaction condition for the preparation of amide startingfrom carboxylic acid and amines.

In another embodiment of the present invention, compounds of generalformula I can be prepared following a different synthetic approach inwhich a compound of general formula XXIV is reacted with a compound offormula XXVI under the transition metal catalyzed cross-couplingreaction conditions, followed by reduction of the double bond —(CH)₂—,leading to a compound of formula I wherein n=2 or n=3 if the reaction isperformed with a compound of formula LG-A₁-B-A₂-C-D-CH₂—(CH)₂-E-H.Alternatively it can be prepared by reaction of a compound of formulaXXI with a compound of formula XXVII under the condition described abovefor the reaction of a compound of formula II with a compound of formulaIII.

Intermediates of formula XXIV and XXI can be prepared by reaction ofcompound of formula XVIII under reductive amination conditions,described above for the reaction of compound of formula XVII with XVIII,starting from compound of formula XXIII and XX respectively.Alternatively compounds of formula XXIV and XXI can be prepared byalkylation of compound XVIII with compound of formula XXV and XXIIrespectively under alkylation condition described above for thepreparation of compound IV by reaction of compound II with compound III.

Compounds of general formula XVIII can be obtained from by simplereduction of the azide of formula XIX. The reaction can be accomplishedby mean of a catalytic hydrogenation in the presence Palladium catalyst.The reaction occurs, in polar solvent such as methanol or ethanol, underhydrogen atmosphere or under hydrogen transfer condition, using forexample 1,4-cyclohexadiene or 1-methyl1,4-cyclohexadiene as source ofhydrogen. The reaction proceeds at room temperature (RT). In case it isperformed under hydrogen transfer conditions higher temperature can berequired.

The azide XIX can be easily prepared from XXIX by the known nucleophilicsubstitution of alkyl bromide with alkaline azide. The reaction proceedsat a temperature ranging from 50 to 80° C. and in a polar solvent suchas for example DMF of NMP and can be accelerated by the presence ofalkaline iodide.

In an additional embodiment of the present invention, compounds offormula I, wherein R₃ is J2 or another group featuring a quaternaryammonium salt, can be prepared reacting the corresponding tertiary amineprecursor of formula I where R₃ is J1 with a compound of formula XXVIII.The reaction proceeds smoothly at RT or higher temperature in solventsuch as DCM, acetonitrile, methanol or AcOEt over a period of timeranging from 1 to 24 hours.

In another embodiment of the present invention, compounds of generalformula XXI can be prepared by reacting an intermediate of generalformula XXIX with an amine of general formula XXX. This reaction is acommon alkylation of amine in which the leaving group LG (normallychlorine, bromine or sulfate) is displaced by a nucleophile like theamine XXX as such or protected at the amine moiety. Several methods toperform this reaction, that normally occurs in a polar solvent at atemperature higher than RT, are described in the literature. A similarreaction can be used for the preparation of a compound of generalformula XXXVII.

It is apparent for those skilled in the art that compounds of generalformula I wherein R3 is J1 or J2 contain three stereogenic centers, asindicated below with the symbol asterisk (*). This means that thestructure of formula I is characterized by eight differentstereoisomers.

Each diastereoisomer can be obtained theoretically by chromatographicseparation of the mixture obtained by reacting racemic mixtures of therequired intermediates. It is clear that this approach it is notconvenient and that it can be used only for the separation of mixturescontaining few diastereoisomers.

In a more convenient approach, the synthesis of each single stereoisomercan be accomplished using, in the reactions described above, onlyenantiomerically pure intermediates.

The enantiomerically pure alcohol required for the preparation ofcompounds of general formula I wherein R3 is J1 or J2 are commerciallyavailable.

The preparation of single enantiomerically pure compounds of generalformula XXIX wherein LG is bromine are described in WO2005/080324,US2005-2222128, WO2004/032921, US2005/215590, and WO2005/092861 (citedby WO2007/107228), all of which are incorporated herein by reference intheir entireties. Enantiomerically pure compounds of general formulaXXXII can be obtained by chiral chromatographic separation of theracemic mixture or starting from enantiomerically pure amine compoundsof general formula XXXI. Intermediate compounds of formula XXXI containsa basic group, it is possible to obtain the two enantiomers by mean ofcrystallization of the diastereomeric salt, obtained by salification ofthe racemic mixture with an enantiomerically pure carboxylic acid.Widely used carboxylic acids used for this purpose are for examplemandelic acid, tartaric acid and its derivatives. The base XXXI isdissolved in a suitable polar solvent and then treated withenantiomerically pure carboxylic acid causing precipitation of one ofthe two diastereoisomeric salts. It could be required to repeat theprocedure several times to obtain the desired level of enantiomericexcess.

Alternatively the amines of formula XXXI can be obtained viaenantioselective synthesis following for example the approach describedin the literature (see Tetrahedron: Asymmetry 13 (2002) 303-310, whichis incorporated herein by reference in its entirety) in which thealdehyde of formula II, wherein R2 is H, is treated first with aenantiomerically pure tert-butyl sulfinimide and then with R₂MgBr orR₂Li (wherein R2 is not H), followed by hydrolysis of the intermediateleading to the formation of enantiomerically enriched compounds offormula XXXI that can be used as such or further purified to increasethe enantiomeric excess.

The racemic amine of general formula XXXI can be prepared in severaldifferent ways, for example by addition of hydroxylamine to a compoundof general formula II followed by the reduction of the oximeintermediate obtained than can be performed under several reactioncondition known for the skilled in the art. For example catalytichydrogenation, or the use of reducing agent such as LiAlH₄ or Zinc inthe presence of ammonium formate are all very efficient method toaccomplished the reduction of oxime to amine.

The available amine of formula XXXI can be easily further derivatizedunder the reaction conditions described above. For example it can betreated with a protected aldehyde of formula III, under the conditionsdescribed for the alkylation of compounds of formula II with compoundsof formula III, leading to compound or general formula XXXIII.Deprotection of the amino group and reaction of compounds of formula XV,lead to the preparation of a compound of general formula XVI.

Alternatively, compounds of general formula I can be prepared coupling acompound of general formula XXXVI with a compound of general formulaXXXVII leading to a compound of general formula I wherein C is —OCO— orC1. This ester or amide can be obtained under different reactioncondition known to the skilled in the art. The reaction requires theactivation of the acid XXXVI with reactant such asN,N′-Dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate(HBTU), (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) or it may be converted into the correspondingacyl chloride. The activated ester can smoothly react, in DCM, pyridineor other aprotic solvents, with compound of formula XXXVII.

Compounds of formula XXXVI can be prepared starting from XXXII viaalkylation with the compound of formula XXXIV, deprotection and reactionwith compound of formula XV. The reaction conditions for this conversionare described above and described in the literature. Acid XXXVI can beeasily reacted with a compound of formula XXXVIII, as described abovefor the reaction with a compound of formula XXXVII, leading to compoundof formula XVI.

A compound of general formula XXXVII can be prepared by reaction of acompound of general formula XXIX with an amine of formula NH₂-A₁-B-A₂-OHor NH₂-A₁-B-A₂-NHR₄, under the reaction conditions described for thereaction of compounds of general formula XXIX with compounds of generalformula XXX.

For all the above, the synthesis of compounds of general formula I canbe performed following several different approaches. In particular itmust be noted that the sequence of reaction required, strongly dependson the nature of the linkers Y and Y1 and on the functional groupspresent on the linker. The example given above for the preparation ofcompounds of formula I wherein C is —OC(O)— or C1, allows a personskilled in the art to appreciate this aspect of the invention.

The invention also provides pharmaceutical compositions of compounds offormula I in admixture with one or more pharmaceutically acceptablecarriers, for example those described in Remington's PharmaceuticalSciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A., which isincorporated herein by reference in its entirety.

Administration of the compounds of the present invention may beaccomplished according to patient needs, for example, orally, nasally,parenterally (subcutaneously, intravenously, intramuscularly,intrasternally and by infusion), by inhalation, rectally, vaginally,topically, locally, transdermally, and by ocular administration.

Various solid oral dosage forms can be used for administering compoundsof the invention including such solid forms as tablets, gelcaps,capsules, caplets, granules, lozenges and bulk powders. The compounds ofthe present invention can be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and known excipients, including suspendingagents, solubilizers, buffering agents, binders, disintegrants,preservatives, colorants, flavorants, lubricants and the like. Timerelease capsules, tablets and gels are also advantageous inadministering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administeringcompounds of the invention, including aqueous and non-aqueous solutions,emulsions, suspensions, syrups, and elixirs. Such dosage forms can alsocontain suitable known inert diluents such as water and suitable knownexcipients such as preservatives, wetting agents, sweeteners,flavorants, as well as agents for emulsifying and/or suspending thecompounds of the invention. The compounds of the present invention maybe injected, for example, intravenously, in the form of an isotonicsterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of theinvention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.

Formulations for vaginal administration can be in the form of cream,gel, paste, foam, or spray formula containing, in addition to the activeingredient, such as suitable carriers, are also known.

For topical administration the pharmaceutical composition can be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear or nose. Topical administration mayalso involve transdermal administration via means such as transdermalpatches.

For the treatment of the diseases of the respiratory tract, thecompounds according to the invention are preferably administered byinhalation.

Inhalable preparations include inhalable powders, propellant-containingmetering aerosols or propellant-free inhalable formulations.

For administration as a dry powder, single- or multi-dose inhalers knownfrom the prior art may be utilized. In that case the powder may befilled in gelatine, plastic or other capsules, cartridges or blisterpacks or in a reservoir.

A diluent or carrier, generally non-toxic and chemically inert to thecompounds of the invention, e.g. lactose or any other additive suitablefor improving the respirable fraction may be added to the powderedcompounds of the invention.

Inhalation aerosols containing propellant gas such as hydrofluoroalkanesmay contain the compounds of the invention either in solution or indispersed form. The propellant-driven formulations may also containother ingredients such as co-solvents, stabilizers and optionally otherexcipients.

The propellant-free inhalable formulations comprising the compounds ofthe invention may be in form of solutions or suspensions in an aqueous,alcoholic or hydroalcoholic medium and they may be delivered by jet orultrasonic nebulizers known from the prior art or by soft-mistnebulizers such as Respimat®.

The compounds of the invention may be administered as the sole activeagent or in combination with other pharmaceutical active ingredientsincluding those currently used in the treatment of respiratorydisorders, among which beta2-agonists, antimuscarinic agents,mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclearfactor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophilelastase (HNE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors,leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs),antitussive agents, mucus regulators, mucolytics,expectorant/mucokinetic modulators, peptide mucolytics, antibiotics,inhibitors of JAK, SYK inhibitors, inhibitors of PI3Kdelta or PI3Kgamma,corticosteroids, and M3-antagonists/PDE4-inhibitors (MAPI).

The dosages of the compounds of the invention depend upon a variety offactors including the particular disease to be treated, the severity ofthe symptoms, the route of administration, the frequency of the dosageinterval, the particular compound utilized, the efficacy, toxicologyprofile, and pharmacokinetic profile of the compound.

Advantageously, the compounds of formula I can be administered forexample, at a dosage comprised between 0.001 and 1000 mg/day, preferablybetween 0.1 and 500 mg/day.

When the compounds of formula I are administered by inhalation route,they are preferably given at a dosage comprised between 0.001 and 500mg/day, preferably between 0.1 and 200 mg/day.

The compounds of formula I may be administered for the prevention and/ortreatment of broncho-obstructive or inflammatory diseases, such asasthma, chronic bronchitis, chronic obstructive pulmonary disease(COPD), bronchial hyperreactivity, cough, emphysema or rhinitis;urological disorders such as urinary incontinence, pollakiuria,cystospasm, chronic cystitis and overactive bladder (OAB);gastrointestinal disorders such as bowel syndrome, spastic colitis,diverticulitis, peptic ulceration, gastrointestinal motility or gastricacid secretion; dry mouth; mydriasis, tachycardia; ophthalmicinterventions cardiovascular disorders such as vagally induced sinusbradycardia.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The LCMS methods A, B, C and D used for the characterization of thecompounds of the present invention are described in the following:

LCMS/HPLC Methods

Method A (10 cm_ESCI_FORMIC): HPLC Setup Solvents: Acetonitrile (Far UVgrade) with 0.1% (V/V) formic acid Water (High purity via PureLab Optionunit) with 0.1% formic acid Column: - Phenomenex Luna 5μ C18 (2), 100 ×4.6 mm. (Plus guard cartridge) Flow Rate: - 2 ml/min Gradient: - A:Water/formic   B: MeCN/formic Time A % B % 0.00 95  5 3.50  5 95 5.50  595 5.60 95  5 6.50 95  5 Typical Injections 2-7ul (concentration ~ 0.2-1mg/ml). UV detection via HP or Waters DAD Start Range (nm)  210  EndRange (nm)   400  Range interval (nm) 4.0 Other wavelength traces areextracted from the DAD data. Optional ELS detection using Polymer LabsELS-1000. MS detection: Micromass ZQ, single quadrapole LC-MS or QuattroMicro LC-MS-MS. Flow splitter gives approximately 300 ul/min to massspec Scan range for MS Data (m/z) Start (m/z) 100 End (m/z) 650 or 1500when required With +ve/−ve switching Ionization is routinely ESCI anoption which gives both ESI and APCI data from a single run. Typical ESIvoltages and temperatures are: Source 120-150 C.  3.5 KV capillary   25V cone Typical APCI voltages and temperatures are: Source 140-160 C.  17uA corona   25 V cone

Method B (HPLC Conditions - 15 cm_Formic_Ascentis_HPLC_CH3CN): HPLCSetup Solvents:- Acetonitrile (Far UV grade) with 0.1% (VN) formic acidWater (High purity via PureLab Ultra unit) with 0.1% formic acidColumn:- Supelco, Ascentis ® Express C18 or Hichrom Halo C18, 2.7 μmC18, 150 × 4.6 mm. Flow Rate:- 1 ml/min Gradient:- A: Water/formic   B:MeCN/formic Time A % B %  0.00 96  4  3.00 96  4  9.00  0 100 13.6  0100 13.7 96  4 15 96  4 Typical Injections 0.2-10 ul Maximum pressuresetting 400 bar. Instrument: Agilent 1100, Binary Pump, Agilent Samplerand Agilent DAD detector Diode array detection: (300 nm, Band Width 200nm; Ref. 450 nm, Band Width 100 nm)

Method C (HPLC Conditions—10 cm_Formic_ACE-AR_HPLC_CH3CN): HPLC SetupSolvents:- Acetonitrile (Far UV grade) with 0.1% (V/V) formic acid Water(High purity via PureLab Ultra unit) with 0.1% formic acid Column:-Hichrom ACE 3 C18-AR mixed mode column 100 × 4.6 mm Flow Rate:- 1 ml/minGradient:- A: Water/formic   B: MeCN/formic Time A % B %  0.00 98  2 3.00 98  2 12.00  0 100 15.4  0 100 15.5 98  2 17 98  2 TypicalInjections 0.2-10 μl Maximum pressure setting 400 bar. Instrument:Agilent 1100, Binary Pump, Agilent Sampler and Agilent DAD detectorDiode array detection: (300 nm, Band Width 200 nm; Ref. 450 nm, BandWidth 100 nm)

Method D (HPLC Conditions - 25 cm_Acidic_Prodigy_HPLC): HPLC SetupSolvents:- Acetonitrile (Far UV grade) with 0.1% formic acid Water (Highpurity via PureLab Option unit) with 0.1% formic acid Column:-Phenominex Prodigy 5μ ODS 3, 250 × 4.6 mm. Flow Rate:- 1 ml/minGradient:- A: Water/formic   B: MeCN/formic Time A % B %  0.00 95.5  4.5 1.0 95.5  4.5 22  0 100 23  0 100 25 95.5  4.5 30 95.5  4.5 TypicalInjections 2-7 ul Instrument: Agilent 1100, Binary Pump, Agilent Samplerand Agilent DAD detector

The intermediate compounds for the synthesis of final compounds ofgeneral formula (I) were obtained through the preparations describedbelow.

Preparation of(R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride

Step 1: 8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one

To a suspension of 5-acetyl-8-(benzyloxy)quinolin-2(1H)-one (19.4 g,66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) wasadded a solution of tetra-n-butylammonium tribromide (Bu₄NBr₃) (54.5 g,113.0 mmol) in anhydrous THF (130 mL) dropwise over 1.5 hours. Theresulting solution was stirred at RT overnight before concentratingunder reduced pressure without heating. The residue was re-dissolved inmethanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL)was added with ice-cooling. The resulting suspension was filtered andthe solid washed with water and air-dried under vacuum. The solid wassuspended in DCM and methanol (1:1 v/v, 100 mL) for 90 minutes. Thesolid was collected by filtration, washed with DCM and air-dried toafford the title compound (18.0 g, 73%).

¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H); 8.51 (d, J=10.0 Hz, 1H);7.94-7.83 (m, 1H); 7.60 (d, J=7.5 Hz, 2H); 7.44-7.27 (m, 4H); 6.79-6.65(m, 1H); 5.53-5.39 (s, 2H); 4.93 (s, 2H)

Step 2: (R)-8-(Benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one

8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol)and(R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(21.3 g, 76.8 mmol) were azeotroped with toluene (×3) then suspended inanhydrous THF (400 mL) under an atmosphere of nitrogen. The suspensionwas cooled to −20° C. (external temperature) and borane dimethyl sulfide(BH₃-Me₂S) complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF)was added by syringe pump over 3 hours. After complete addition thereaction mixture was stirred for one hour before quenching with methanol(25 mL). The reaction was warmed to RT over 20 minutes. The mixture wasconcentrated under reduced pressure and the residue was suspended inaqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for18 hours. After this time the solid was collected by filtration andwashed with water (3×100 mL). The solid was partially dissolved in ethylacetate and heated at reflux for 2 hours. The remaining solid wasremoved by hot filtration and the filtrate was evaporated to afford thetitle compound. The solid collected from the hot ethyl acetate was againpartially dissolved in ethyl acetate and heated at reflux for 2 hoursthen filtered to give filtrate containing pure product. This process wasrepeated four more times. The combined solid was recrystallised fromethyl acetate and petroleum ether to afford the title compound (20.0 g,76%).

¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H); 8.19 (d, J=9.9 Hz, 1H); 7.58(d, J=7.5 Hz, 2H); 7.41-7.36 (m, 2H); 7.34-7.29 (m, 1H); 7.23-7.19 (m,2H); 6.57 (d, J=9.8 Hz, 1H); 5.94 (d, J=4.7 Hz, 1H); 5.31 (s, 2H);5.25-5.19 (m, 1H); 3.71-3.58 (m, 2H).

Step 3:(R)-8-(Benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one

2,6-Lutidine (6.9 mL, 59.5 mmol) was added to a solution of(R)-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one (10.1 g,27.0 mmol) in DCM (100 mL) at 0° C. The reaction mixture was stirred for5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate(tBuMe₂SiOtf) (13.0 mL, 56.8 mmol) was added dropwise over 15 minutes.The mixture was stirred at 0° C. for 30 minutes, followed by RTovernight. After this time the reaction was quenched with saturatedaqueous sodium bicarbonate solution and extracted with DCM (×3). Thecombined organic extracts were dried (magnesium sulfate), filtered andconcentrated under reduced pressure. Iso-hexane (500 mL) was added tothe crude material and the resulting solid collected by filtration. Thesolid was recrystallised from ethyl acetate and petroleum ether (40:60)to afford the title compound (11.3 g, 85%).

¹H NMR (400 MHz, CDCl₃): δ 9.19 (s, 1H); 8.23 (dd, J=9.9, 4.4 Hz, 1H);7.43 (d, J=4.6 Hz, 5H); 7.17 (dd, J=8.3, 4.5 Hz, 1H); 7.03 (dd, J=8.2,4.4 Hz, 1H); 6.71 (dd, J=9.9, 3.7 Hz, 1H); 5.18 (d, J=4.5 Hz, 3H);3.63-3.56 (m, 1H); 3.49 (dd, J=10.4, 4.8 Hz, 1H); 0.88 (t, J=4.4 Hz,9H); 0.14 (d, J=4.4 Hz, 3H); −0.11 (d, J=4.4 Hz, 3H).

Step 4:(R)-5-(2-Azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one

(R)-8-(Benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one(10.0 g, 20.5 mmol) was dissolved in dimethyl formamide (180 mL) andwater (20 mL). Sodium iodide (3.39 g, 22.6 mmol) and sodium azide (1.47g, 22.6 mmol) were added sequentially. The reaction mixture was stirredat RT until all the solid was in solution. The solution was heated at80° C. for 40 hours then cooled to RT and diluted with ethyl acetate(300 mL). The mixture was washed with water, brine (×2) and the organicextract was dried (magnesium sulfate), filtered and concentrated underreduced pressure. The crude residue was triturated with iso-hexane toafford the desired compound (8.16 g, 88%). Used without furtherpurification in the next step.

¹H NMR (400 MHz, CDCl₃): δ 9.19 (s, 1H), 8.18 (d, J=9.9 Hz, 1H),7.45-7.36 (m, 4H), 7.20 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.70(dd, J=9.9, 2.2 Hz, 1H), 5.19-5.13 (m, 3H), 3.48 (dd, J=12.7, 8.1 Hz,1H), 3.26 (dd, J=12.7, 3.8 Hz, 1H), 0.89 (s, 9H), 0.14 (s, 3H), −0.11(s, 3H).

Step 5: (R)-5-(2-Amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-onehydrochloride

To a solution of(R)-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(4.50 g, 10.0 mmol) in ethanol (50 mL) was added 10% palladium oncharcoal (4.50 g) followed by 1-methyl-1,4-cyclohexadiene (11.0 mL, 97.9mmol). The reaction was warmed to 60° C. and then stirred at 60° C. for2 hours. The reaction mixture was allowed to cool and filtered through apad of celite. The filtercake was washed with further ethanol and thefiltrate was evaporated at reduced pressure. The residue was evaporatedfrom iso-propanol (×2) and dissolved in iso-propanol (30 mL).HCl-dioxane (4 M, 50 mL, 200 mmol) was added and the reaction mixturestirred at RT for 18 hours. The resultant suspension was filtered, thefiltercake washed with ether and the solid dried under vacuum in thepresence of P₂O₅ to afford the title compound (1.65 g, 62%).

¹H NMR (400 MHz, MeOD): δ 7.71 (d, J=9.8 Hz, 1H), 6.57 (d, J=8.2 Hz,1H), 6.31 (d, J=8.2 Hz, 1H), 6.02 (dd, J=9.8, 6.5 Hz, 1H), 4.58 (dd,J=9.6, 3.5 Hz, 1H), 2.47-2.31 (m, 2H).

Synthesis of Compounds 1 to 17

Example 12-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(Compound 1)

Step 1: N-((3-hydroxyphenyl)(phenyl)methyl)formamide

3-Hydroxybenzophenone (25 g, 126.1 mmol) in formamide (130 mL, 3.3 mmol)was heated to 180° C. for 18 hours. The reaction was allowed to coolslightly then poured into ice-cooled water and stirred for 30 minutes,filtered and washed with water. The solid was stirred in water (60 mL)and ethanol (60 mL) and heated to 50° C. for 1 hour, then allowed tocool. The solid was filtered and washed with water to give the titlecompound as a brown solid (33.94 g, 118%).

¹H NMR (400 MHz, CD₃OD): δ 7.39-7.28 (m, 5H); 7.21-7.13 (m, 1H); 6.79(d, J=7.78 Hz, 1H); 6.73-6.68 (m, 2H); 5.45 (s, 1H).

Step 2: 3-(Amino(phenyl)methyl)phenol hydrochloride

Methanol (125 mL), was cooled to 0° C. and acetyl chloride (17.8 mL)added dropwise to give a 2M solution of methanolic hydrogen chloride.N-((3-hydroxyphenyl)(phenyl)methyl)formamide was stirred at 40° C. for1.5 hours with the 2M methanolic hydrogen chloride. The solvent wasremoved under reduced pressure and the residue re-dissolved in methanoland the solvent removed under reduced pressure. This process wasrepeated three times to give the title compound as a brown solid (29.09g, 97.9%)

¹H NMR (400 MHz, DMSO-d₆): δ 9.76 (s, 1H); 9.07 (s, 3H); 7.59-7.53 (m,2H); 7.51-7.37 (m, 3H); 7.26 (t, J=7.89 Hz, 1H); 6.99 (d, J=7.75 Hz,1H); 6.90 (t, J=1.97 Hz, 1H); 6.81 (dd, J=8.10, 2.32 Hz, 1H); 5.58 (d,J=5.82 Hz, 1H).

Step 3: tert-Butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate

3-(Amino(phenyl)methyl)phenol hydrochloride (29.09 g, 123.4 mmol) indichloromethane (450 mL) was cooled to 0° C. and diisopropylethylamine(65.9 mL, 370.2 mmol) and di-tert-butyl dicarbonate (59.2 g, 271.5 mmol)was added slowly. The reaction was stirred at 0° C. for 2 hours thenwarmed to RT over 16 hours. The solvent was removed and compoundpurified through a silica plug, eluting with 0-20% ethyl acetate iniso-hexane to give a black oil. To this mixture in methanol (300 mL) wasadded potassium carbonate (51 g, 370.2 mmol) and stirred at RT for 16hours. The suspension was filtered and the filtrate was evaporated atreduced pressure and the residue re-dissolved in ethyl acetate (370 mL).Silica (73 g) was added and the suspension was stirred for 30 minutes,filtered, and the filter cake washed with further ethyl acetate. Thefiltrate was evaporated to dryness. The dark solid residue was dissolvedin ethyl acetate (200 m L) was charcoal added and the suspension washeated under refluxed for 1 hour. The suspension was filtered throughcelite and solvent removed at reduced pressure. The dark solid wasdissolved in dichloromethane and iso-hexane added then solventevaporated (repeated 3 times) to give the title compound as a yellowsolid (34.81 g, 92%).

¹H NMR (400 MHz, CDCl3): δ 7.36-7.16 (m, 6H); 6.80 (d, J=7.79 Hz, 1H);6.74-6.69 (m, 2H); 5.83 (s, 1H); 5.15 (s, 1H); 1.53-1.30 (s, 9H).

Step 4: (S)-tert-Butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate

The racemic mixture from step 3 was purified by SFC using a CHIRALPAK®AD 20 μM 250×110 mm column using n-heptane/2-propanol/diethylamine(60/40/0.1) as eluant with a flow rate of 570 ml/min at 25° C. From 54.1g of crude material (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate (R_(t)=8.5-8.6 min, 23.9 g,99.2 e.e.) was obtained.

Step 5: (S)-Methyl4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)-methyl)benzoate

A mixture of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate(3.20 g, 10.7 mmol), methyl 4-(bromomethyl)benzoate (2.70 g, 11.8 mmol)and potassium carbonate (2.20 g, 16.1 mmol) in acetonitrile (54 mL) wasstirred at RT for 16 hours. The reaction mixture was concentrated atreduced pressure and the residue partitioned between ethyl acetate andwater. The aqueous phase was extracted with further ethyl acetate andthe combined organic extracts combined, dried with anhydrous magnesiumsulfate, filtered and the solvent evaporated at reduced pressure. Theresidue was recrystallised from ethyl acetate and iso-hexane to affordthe title compound as a white solid (3.25 g, 68%).

¹H NMR (400 MHz, CDCl3): δ 8.04 (d, J=8.2 Hz, 2H); 7.46 (d, J=8.2 Hz,2H); 7.34-7.20 (m, 6H); 6.90-6.81 (m, 3H); 5.87 (s, 1H); 5.13 (s, 1H);5.07 (s, 2H); 3.92 (s, 3H); 1.44 (s, 9H).

Step 6: (S)-Methyl 4-((3-(amino(phenyl)methyl)phenoxy)methyl)benzoatehydrochloride

To a solution of methyl4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate(3.21 g, 7.20 mmol) in methanol (36 mL) was added hydrogen chloride indioxane (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at RTfor 16 hours. The solvent was removed at reduced pressure to afford thetitle compound (2.65 g, >95%).

¹H NMR (400 MHz, CDCl3): δ 9.21 (s, 2H); 8.03 (d, J=8.1 Hz, 2H); 7.64(d, J=8.1 Hz, 2H); 7.59 (d, J=7.6 Hz, 2H); 7.49-7.34 (m, 5H); 7.17 (d,J=7.7 Hz, 1H); 7.06 (dd, J=8.3, 2.4 Hz, 1H); 5.64 (s, 1H); 5.28 (s, 2H);3.91 (s, 3H).

Step 7: Methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate

To a stirred solution of (S)-methyl4-((3-(amino(phenyl)methyl)phenoxy)methyl)-benzoate hydrochloride (12.0g, 31.3 mmol) in pyridine (100 mL) at 0° C. was added portion-wise(R)-quinuclidin-3-yl carbonochloridate (8.50 g, 37.5 mmol). The reactionwas stirred at 0° C. for 1 hour and then allowed to warm to RT for 16hours. Water was added to the reaction mixture and extracted with ethylacetate (×3). The combined extracts were washed with brine, dried(sodium sulfate), filtered and the solvent evaporated at reducedpressure. The crude material was purified by chromatography on a KP-NHBiotage cartridge eluting with 0-20% methanol in ethyl acetate to affordthe title compound (10.3 g, 66%).

Step 8:4-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)benzoicacid

To a stirred solution of methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(2.27 g, 4.50 mmol) in THF (23 mL) was added an aqueous solution oflithium hydroxide (2.0 M, 9.0 ml, 18.0 mmol). The mixture was stirred atRT for 16 hours. The pH of the reaction mixture was adjusted to 6 by theaddition of 4M aqueous hydrochloric acid. The mixture was then extractedwith 10% methanolic ethyl acetate (×2) and the combined organic extractsevaporated at reduced pressure. The residue was then dissolved inethanol and re-evaporated at reduced pressure to afford the titlecompound as a pale yellow solid (1.85 g, 84%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J=9.4 Hz, 1H); 7.99 (d, J=7.9 Hz,2H); 7.58 (d, J=8.0 Hz, 2H); 7.42-7.26 (m, 6H); 7.09 (s, 1H); 7.02-6.91(m, 2H); 5.87 (d, J=9 Hz, 1H); 5.21 (s, 2H); 4.76 (s, 1H); 3.98-2.72 (m,6H); 2.12-1.54 (m, 5H).

Step 9: -(2-Hydroxyethoxy)-3-methylbenzaldehyde

To a stirred solution of 4-hydroxy-3-methyl-benzaldehyde (0.545 g, 4.00mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.97 mmol).The reaction mixture was stirred at RT for 5 minutes and then a solutionof ethylene carbonate (0.705 g, 8.00 mmol) in DMF (2 mL) was added. Theresultant mixture was heated at 80° C. for 90 hours. The reactionmixture was allowed to cool and diluted with ethyl acetate and water.The organic phase was removed, washed with brine (×2), dried (magnesiumsulfate), filtered and the solvent evaporated at reduced pressure toafford the title compound (0.677 g, 94%).

¹H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H); 7.72-7.70 (m, 2H); 6.95-6.93(m, 1H); 4.20-4.18 (m, 2H); 4.04-4.03 (m, 2H); 2.29 (s, 3H); 1.98 (s,1H).

Step 10: 2-(4-Formyl-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate

To a stirred solution of4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid (0.778 g, 1.49 mmol) in DMF (6 mL) was addeddi-iso-propylethylamine (0.649 mL, 1.79 mmol) and HATU (0.679 g, 1.79mmol) and the mixture stirred at RT for 20 minutes. To the resultantsolution was added a solution of4-(2-hydroxyethoxy)-3-methylbenzaldehyde (0.670 g, 3.72 mmol) in DMF (2mL). The mixture was stirred at RT for 18 hours. The mixture was dilutedwith ethyl acetate washed with 10% aqueous potassium carbonate, brine(×2), dried (magnesium sulfate), filtered and the solvent evaporated atreduced pressure. The residue was loaded onto an SCX-2 cartridge andeluted with acetonitrile (4 column volumes) and then 10%triethylamine/acetonitrile (4 column volumes).

The 10% triethylamine/acetonitrile fractions analyzed by TLC and productcontaining fractions combined and evaporated at reduced pressure.Material used directly in the next step with no further purification.

Step 11:2-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (Compound 1)

To a suspension of(R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride(0.211 g, 0.83 mmol) in methanol (6 mL) was added triethylamine (0.229mL, 1.65 mmol). The mixture was stirred for 10 minutes and then asolution of 2-(4-formyl-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(0.445 g, 0.69 mmol) in methanol (2 mL) was added. The mixture wasstirred at RT for 1 hour. Sodium triacetoxyborohydride (0.292 g, 1.38mmol) followed by acetic acid (0.188 mL, 3.28 mmol) added and thereaction continued for a further 18 hours. The reaction mixture wasquenched with water and evaporated at reduced pressure. The residuedissolved in iso-butanol and washed with water. The organic phase wasevaporated at reduced pressure and the crude material was purified byreverse phase preparative HPLC to afford the title compound (0.065 g,11%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.29-8.20 (m, 2H); 8.10 (d, J=9.9 Hz, 1H);7.97 (d, J=8.0 Hz, 2H); 7.57 (d, J=8.0 Hz, 2H); 7.32-7.18 (m, 6H);7.17-7.01 (m, 4H); 6.98-6.85 (m, 4H); 6.47 (d, J=9.9 Hz, 1H); 5.81 (s,1H); 5.17 (s, 2H); 5.09 (dd, J=7.9, 4.7 Hz, 1H); 4.60 (d, J=16.8 Hz,3H); 4.31 (d, J=5.0 Hz, 2H); 3.71 (s, 2H); 3.12 (m, 1H); 2.81-2.52 (m,6H); 2.09 (s, 4H); 1.92 (s, 1H); 1.69-1.26 (m, 4H).

An alternative method for preparing the requisite alcohol is highlightedby the synthesis of 3-chloro-4-(2-hydroxyethoxy)-5-methoxybenzaldehyde.

Preparation of 3-chloro-4-(2-hydroxyethoxy)-5-methoxybenzaldehyde

To a suspension of sodium hydride (60% dispersion in mineral oil, 0.24g, 6.00 mmol) in DMF (8 mL) was added a solution of 5-chlorovanillin(0.746 g, 4.00 mmol) in DMF (2 mL). The reaction mixture was stirred atRT for 20 minutes and 2-bromoethanol (0.42 mL, 5.93 mmol) added. Thereaction mixture was heated at 50° C. for 90 hours. The reaction mixturewas diluted with ethyl acetate and washed with water, brine (×2), dried(magnesium sulfate), filtered and the solvent evaporated at reducedpressure. The residue was purified by flash column chromatographyeluting with 0-50% ethyl acetate in iso-hexane to afford the titlecompound (0.413 g, 48%).

¹H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H); 7.53 (d, J=1.6 Hz, 1H); 7.38(d, J=1.6 Hz, 1H); 4.29-4.27 (m, 2H); 3.96 (s, 3H); 3.90-3.85 (m, 2H);2.77 (t, d, J=6.4 Hz, 1H).

The following compounds were prepared in the same fashion coupling therequisite alcohol generated in Step 9 with the acid from Step 8 andusing the product in the subsequent steps.

Compound number Linker  2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

Synthesis of Compounds 18 to 21

Example 24-(2-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)ethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)-methyl)phenoxy)methyl)benzoate(Compound 18)

Step 1: Methyl 4-(2-methoxyvinyl)benzoate

To an ice-cooled suspension of (methoxymethyl)triphenylphosphoniumchloride (6.48 g, 20.0 mmol) in THF (40 mL) was added portion wisesodium hydride (60% dispersion in mineral oil, 0.88 g, 22.0 mmol). Thereaction mixture was stirred at this temperature for 10 minutes followedby 50 minutes at RT. A solution of methyl 4-formyl benzoate (1.16 g,10.0 mmol) in THF (10 mL) was added and the mixture stirred at RT for 18h. The reaction mixture was quenched with saturated aqueous sodiumhydrogen carbonate and extracted with DCM. The organic phase was pouredthrough a hydrophobic fit and the solvent evaporated at reducedpressure. The residue was purified by flash column chromatographyeluting with 0-10% ethyl acetate in iso-hexane to afford the titlecompound (1.36 g, 71%).

¹H NMR (400 MHz, CDCl3): Mixture of isomers: δ 7.98-7.90 (m, 2H);7.63-7.59 (m, 1H); 7.29-7.25 (m, 1H); 7.17 (d, J=13.0 Hz, 0.5H); 6.25(d, J=7.0 Hz, 0.5H); 5.82 (d, J=13.0 Hz, 0.5H); 5.31-5.25 (m, 0.5H);3.90 (s, 3H); 3.83 (s, 1.5H); 3.72 (s, 1.5H).

Step 2: Methyl 4-(2,2-dimethoxyethyl)benzoate

To a solution of methyl 4-(2-methoxyvinyl)benzoate (1.36 g, 7.08 mmol)in methanol (30 mL) was added para-toluenesulfonic acid monohydrate(pTSA) (0.135 g, 0.71 mmol) and the reaction mixture heated under refluxfor 18 hours. The solvent was evaporated at reduced pressure. Theresidue was partitioned between DCM and 10% aqueous potassium carbonate.The organic phase was poured through a hydrophobic fit and the solventevaporated at reduced pressure. The crude material was used in the nextstep without further purification.

Step 3: (4-(2,2-Dimethoxyethyl)phenyl)methanol

To a cooled (−78° C.) solution of methyl 4-(2,2-dimethoxyethyl)benzoate(assume 7.08 mmol) in THF (30 mL) was added drop wise a solution oflithium aluminium hydride (2.0 M in THF, 3.50 mL, 7.00 mmol). Thereaction mixture was allowed to warm to RT over 4 hours. The mixture wassequentially treated with water (0.266 mL), 2M aqueous sodium hydroxide(0.266 mL) and water (3×0.266 mL). The mixture was diluted with ethylacetate and magnesium sulfate added. The mixture was stirred at RT for 1hour and then filtered through celite. The filter cake was washed withfurther ethyl acetate and the filtrates combined. The solvent wasevaporated at reduced pressure and the residue was purified by flashcolumn chromatography eluting with 0-30% ethyl acetate in iso-hexane toafford the title compound (0.854 g, 62%).

¹H NMR (400 MHz, CDCl3): δ 7.32-7.30 (m, 2H); 7.26-7.23 (m, 2H); 4.68(d, J=5.6 Hz, 2H); 4.55-4.52 (m, 1H); 3.34 (s, 6H); 2.92 (d, J=5.6 Hz,1H); 1.28-1.24 (m, 1H).

Step 4:3-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoicacid

The title compound was prepared as described in Example 1 Steps 5through 8 with methyl 3-(bromomethyl)benzoate replacing methyl4-(bromomethyl)benzoate in Step 5.

Step 5: 4-(2,2-Dimethoxyethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate

The title compound was prepared as described in Example 1 Step 10 with(4-(2,2-dimethoxyethyl)phenyl)methanol and3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoicacid replacing 4-(2-hydroxyethoxy)-3-methylbenzaldehyde and methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoatehydrochloride respectively.

Step 6: 4-(2-Oxoethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate

To a stirred solution of 4-(2,2-dimethoxyethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(0.100 g, 0.15 mmol) in acetone (5 mL) was added para-toluenesulfonicacid monohydrate (0.086 g, 0.45 mmol) and the mixture stirred at RT for1 hour. The reaction mixture was diluted with saturated sodium hydrogencarbonate and extracted with ethyl acetate. The combined organicextracts were dried (magnesium sulfate), filtered and the solventevaporated at reduced pressure. The residue was used in the next stepwith no further purification.

Step 7:4-(2-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)ethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)-methyl)phenoxy)methyl)benzoate(Compound 18)

The title compound was prepared as described in Example 1 Step 11 with4-(2-oxoethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoatereplacing 2-(4-formyl-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate.

¹H NMR (400 MHz, DMSO-d₆): δ 8.28-8.19 (m, 3H); 8.17 (d, J=9.9 Hz, 1H);8.05 (s, 1H); 7.94 (d, J=7.8 Hz, 1H); 7.72 (d, J=7.7 Hz, 1H); 7.58-7.52(m, 1H); 7.38 (d, J=7.8 Hz, 2H); 7.31-7.17 (m, 7H); 7.10-7.02 (m, 2H);6.96-6.86 (m, 3H); 6.51 (d, J=9.9 Hz, 1H); 5.81 (d, J=9.0 Hz, 1H); 5.33(s, 2H); 5.16 (s, 2H); 5.07 (dd, J=7.5, 4.8 Hz, 1H); 4.57 (s, 1H); 3.10(s, 1H); 2.86-2.65 (m, 8H); 2.50 (m, 4H); 1.90 (s, 1H); 1.79 (s, 1H);1.46 (t, J=49.4 Hz, 3H).

The following compounds were prepared in an analogous manner to Example2 coupling the requisite alcohol (prepared as described in Example 2Steps 1 to 3) to the requisite acid as described in Example 2 Step 5 andthe subsequent product used in Example 2 Step 6 and 7.

Cpd. Requisite alcohol Requisite acid 19

20

21

Cpd. Structure 19

20

21

Synthesis of Compounds 22 to 31

Example 33-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(Compound 22)

Step 1: Methyl 3-(1,3-dioxolan-2-yl)benzoate

A mixture of methyl 3-formylbenzoate (2.5 g, 15.2 mmol), ethylene glycol(4.2 mL, 75 mmol) and para-toluenesulfonic acid monohydrate (0.29 g,1.52 mmol) in toluene (60 mL) was heated at reflux under Dean and Starkconditions for 4 hours. The reaction mixture was diluted with ethylacetate and washed sequentially with saturated sodium hydrogen carbonateand brine. The organic phase was dried (magnesium sulfate), filtered andthe solvent evaporated at reduced pressure to afford the title compound(3.09 g, 98%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.05-7.95 (m, 2H), 7.72 (d, 1H), 7.61-7.52(m, 1H), 5.82 (s, 1H), 4.11-3.94 (m, 4H), 3.87 (s, 2H).

Step 2: (3-(1,3-Dioxolan-2-yl)phenyl)methanol

The title compound was prepared as described in Example 2 Step 3 withmethyl 3-(1,3-dioxolan-2-yl)benzoate replacing methyl4-(2,2-dimethoxyethyl)benzoate.

¹H NMR (400 MHz, DMSO-d₆): δ 7.40 (s, 1H), 7.37-7.27 (m, 3H), 5.77-5.68(m, 1H), 5.21 (t, 1H), 4.53-4.46 (m, 2H), 4.09-3.90 (m, 4H).

Step 3: 3-(1,3-Dioxolan-2-yl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate

The title compound was prepared as described in Example 1 Step 10 with(3-(1,3-dioxolan-2-yl)phenyl)methanol replacing4-(2-hydroxyethoxy)-3-methylbenzaldehyde.

Step 4; 3-Formylbenzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate

To a stirred solution of 3-(1,3-dioxolan-2-yl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(0.32 g, 0.57 mmol) in THF (8 mL) was added 2M aqueous hydrochloric acid(8 mL). The reaction mixture was stirred at RT for 1 hour. The mixturewas diluted with ethyl acetate and was washed sequentially withsaturated aqueous sodium hydrogen carbonate and brine. The organicextract was dried (magnesium sulfate), filtered and the solventevaporated at reduced pressure. The residue was used in the next stepwith no further purification.

Step 5:3-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(Compound 22)

The title compound was prepared as described in Example 1 Step 11 with3-formylbenzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoatereplacing 2-(4-formyl-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate.

¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (s, 2H); 8.17 (d, J=9.9 Hz, 1H); 8.04(d, J=8.0 Hz, 2H); 7.61 (d, J=8.0 Hz, 2H); 7.48 (s, 1H); 7.41-7.22 (m,9H); 7.13-7.07 (m, 2H); 7.01-6.90 (m, 3H); 6.51 (d, J=9.9 Hz, 1H); 5.86(d, J=8.6 Hz, 1H); 5.39 (s, 2H); 5.23 (s, 2H); 5.12 (dd, J=7.9, 4.3 Hz,1H); 4.63 (s, 1H); 3.85 (s, 2H); 3.17 (d, J=14.5 Hz, 1H); 2.83-2.67 (m,7H); 1.96 (m, 2H); 1.66 (s, 1H); 1.53 (s, 1H); 1.39 (s, 1H).

The following compounds were prepared in an analogous manner to Example3 coupling the requisite alcohol (prepared as described in Example 3Steps 1 to 2) to the requisite acid as described in Example 3 Step 3 andthe subsequent product used in Example 3 Step 4 and 5.

Cpd. Requisite alcohol Requisite acid 23

24

25

26

27

28

29

30

31

31A

31B

31C

Cpd. Structure 23

24

25

26

27

28

29

30

31

31A

31B

31C

The following compounds were prepared in an analogous manner to Example3 coupling the requisite alcohol (as described below) to the requisiteacid as described in Example 3 Step 3 and the subsequent product used inExample 3 Step 4 and 5.

Cpd. Requisite alcohol Requisite acid 32

33

34

35

Cpd. Structure 32

33

34

35

The synthesis of the requisite alcohols are detailed below.

The synthesis of the requisite alcohol for Compound Number 32:3-(4-(Diethoxymethyl)-phenyl)propan-1-ol.

Step 1: (E)-Methyl 3-(4-(diethoxymethyl)phenyl)acrylate

A solution of 4-(diethoxy)benzaldehyde (2.08 g, 10.0 mmol) and methyl(triphenylphosphoranylidene)acetate (3.68 g, 11.0 mmol) in toluene (30mL) was heated under reflux for 18 hours. The solvent was evaporated atreduced pressure. The residue was by flash column chromatography elutingwith 0-15% ethyl acetate in iso-hexane to afford the title compound(2.41 g, 91%).

¹H NMR (400 MHz, CDCl3): δ 7.72 (d, J=16 Hz, 1H); 7.54-7.48 (m, 4H);6.46 (d, J=16 Hz, 1H); 5.51 (s, 1H); 3.81 (s, 3H); 3.65-3.50 (m, 4H);1.28-1.22 (m, 6H).

Step 2: Methyl 3-(4-(diethoxymethyl)phenyl)propanoate

1-Methyl-1,4-cyclohexadiene (10.0 mL, 89 mmol) was added to a suspensionof (E)-methyl 3-(4-(diethoxymethyl)phenyl)acrylate (2.41 g, 9.13 mmol)and 10% palladium on carbon (2.4 g) in ethanol (40 mL). The reactionmixture was heated at 60° C. for 1.5 hours. The reaction mixture wasfiltered through celite and the filter cake washed with further ethanol.The solvent was evaporated at reduced pressure to afford the titlecompound (2.15 g, 89%).

¹H NMR (400 MHz, CDCl3): δ 7.40 (m, 2H); 7.20-7.18 (m, 2H); 5.46 (s,1H); 3.73 (s, 3H); 3.70-3.48 (m, 4H); 2.97-2.92 (m, 2H); 2.69-2.60 (m,2H); 1.26-1.23 (m, 6H).

Step 3: 3-(4-(Diethoxymethyl)phenyl)propan-1-ol

The title compound was prepared as described in Example 2 Step 3 withmethyl 4-(2,2-dimethoxyethyl)benzoate replacing methyl4-(2,2-dimethoxyethyl)benzoate.

¹H NMR (400 MHz, CDCl3): δ 7.39 (d, J=8.4 Hz, 2H); 7.20-7.18 (m, 2H);5.47 (s, 1H); 3.69-3.49 (m, 6H); 2.73-2.69 (m, 2H); 1.90-1.85 (m, 2H);1.28-1.24 (m, 6H).

The synthesis of the requisite alcohol for Compound 33:2-(4-(1,3-Dioxolan-2-yl)phenyl)ethanol.

Step 1: Methyl 2-(4-formylphenyl)acetate

Acetyl chloride (5 mL) was added to an ice-cooled solution of4-(hydroxymethyl)phenylacetic acid (5.78 g, 34.8 mmol) in methanol (200mL). The reaction mixture allowed to warm to RT at stirred at thistemperature for 42 hours. The solvent was evaporated at reduced pressureand the residue dissolved in DCM (100 mL). Manganese dioxide (29.47 g,339 mmol) was added and the resultant suspension stirred at RT for 18hours. The suspension was filtered through celite and the filter cakewashed with further DCM. The solvent was evaporated at reduced pressureand the residue was purified by flash column chromatography eluting with0-25% ethyl acetate in iso-hexane to afford the title compound (1.72 g,28%).

¹H NMR (400 MHz, CDCl3): δ 10.0 (s, 1H); 7.87-7.83 (m, 2H); 7.46 (d, J=8Hz, 2H); 3.69-3.65 (m, 5H).

Step 2: 2-(4-(1,3-Dioxolan-2-yl)phenyl)ethanol

Methyl 2-(4-formylphenyl)acetate (1.72 g, 9.66 mmol) was dissolved inethylene glycol (2.3 mL) and triethyl orthoformate (1.8 mL).Tetrabutylammonium tribromide (0.048 g) added and the reaction stirredat RT for 1 hour. Further tetrabutylammonium tribromide (0.434 g) addedand the reaction stirred for 1 hour. The reaction mixture was dilutedwith ethyl acetate and washed with water and brine. The organic phasewas dried (magnesium sulfate), filtered and the solvent evaporated atreduced pressure. The residue was purified by flash columnchromatography eluting with 0-15% ethyl acetate in iso-hexane to affordimpure methyl 2-(4-(1,3-dioxolan-2-yl)phenyl)acetate (0.84 g). Thismaterial was dissolved in THF (15 mL) and cooled to −78° C. A solutionof lithium aluminium hydride (1.0 M in THF, 6.00 mL, 6.00 mmol) wasadded drop-wise. The reaction mixture was allowed to warm to RT over 18hours. The mixture was sequentially treated with water (0.228 mL), 2Maqueous sodium hydroxide (0.228 mL) and water (3×0.228 mL). The mixturewas diluted with ethyl acetate and magnesium sulfate added. The mixturewas stirred at RT for 1 hour and then filtered through celite. Thefilter cake was washed with further ethyl acetate and the filtratescombined. The solvent was evaporated at reduced pressure and the residuewas purified by flash column chromatography eluting with 0-40% ethylacetate in iso-hexane to afford the title compound (0.315 g, 17%).

¹H NMR (400 MHz, CDCl3): 7.44-7.42 (m, 21-1); 7.26-7.24 (m, 2H); 5.80(s, 1H); 4.17-4.00 (m, 4H); 3.88-3.83 (m, 2H); 2.89-2.87 (m, 2H);1.39-1.34 (m, 1H).

The synthesis of the requisite alcohol for Compound Number 34:(1-(3-(1,3-Dioxolan-2-yl)propyl)-1H-pyrazol-4-yl)methanol.

Step 1: Ethyl 1-(3-(1,3-dioxolan-2-yl)propyl)-1H-pyrazole-4-carboxylate

To an ice-cooled stirred solution of ethyl 1H-pyrazole-4-carboxylate(2.0 g, 14.3 mmol) in DMF (10 mL) was added sodium hydride (60%dispersion in mineral oil, 0.68 g, 17.1 mmol). The reaction mixture wasallowed to warm to RT over 20 minutes and 2-(2-bromoethyl)-1,3-dioxolane(2.84 g, 15.7 mmol) added. The reaction mixture was heated at 60° C. for16 hours. The reaction was partitioned between ethyl acetate and brine.The organic phase was washed with further brine, dried (magnesiumsulfate), filtered and the solvent evaporated at reduced pressure. Theresidue was purified by flash column chromatography eluting with 0-100%ethyl acetate in iso-hexane to afford the title compound (2.14 g, 59%).

¹H NMR (400 MHz, CDCl3): δ 7.91 (d, J=4.3 Hz, 2H); 4.92-4.83 (m, 1H);4.33-4.25 (m, 4H); 4.03-3.80 (m, 4H); 2.29-2.22 (m, 2H); 1.39-1.31 (m,3H).

Step 2: (1-(3-(1,3-Dioxolan-2-yl)propyl)-1H-pyrazol-4-yl)methanol

The title compound was prepared as Example 2 Step 2 with ethyl1-(3-(1,3-dioxolan-2-yl)propyl)-1H-pyrazole-4-carboxylate replacingmethyl 4-(2-methoxyvinyl)benzoate.

¹H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H); 7.60-7.44 (m, 1H); 4.94-4.84(m, 1H); 4.61-4.48 (m, 4H); 4.06-3.82 (m, 4H); 2.31-2.21 (m, 2H);1.70-1.64 (m, 1H).

The synthesis of the requisite alcohol for Compound Number 35:1-(2-Hydroxyethyl)-1H-pyrazole-4-carbaldehyde.

1H-Pyrazole-4-carboxaldehyde (0.50 g, 5.21 mmol), 2-bromoethanol (1.30g, 10.41 mmol) and potassium carbonate (0.79 g, 5.73 mmol) combined withacetonitrile (5 mL) in a microwave vial. The microwave vial was heatedat 150° C. in a microwave for 30 minutes. The reaction mixture wasfiltered and the solvent evaporated at reduced pressure. The residue waspurified by flash column chromatography eluting with 0-100% ethylacetate in iso-hexane to afford the title compound (0.50 g, 69%).

¹H NMR (400 MHz, CDCl3): δ 9.86 (s, 1H); 8.02 (s, 1H); 7.99 (s, 1H);4.33-4.25 (m, 2H); 4.05 (t, J=4.8 Hz, 2H).

Example 44-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)-carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylate(Compound 36)

Step 1: Methyl1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-3-carboxylate

To an ice-cooled solution of methyl5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylate (0.60 g, 3.51 mmol)and triethylamine (1.22 mL, 8.77 mmol) in DCM (10 mL) was addedmethanesulfonyl chloride (0.41 mL, 5.26 mmol). The reaction mixture wasstirred at this temperature for 15 minutes and the coolant removed. Thereaction mixture was stirred at RT for 1 hour. The reaction mixture wasdiluted with DCM and washed with water and brine. The organic phase wasdried (magnesium sulfate), filtered and the solvent evaporated atreduced pressure. The crude material was used in the next step withoutfurther purification.

Step 2: (S)-Methyl5-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)methyl)-1-methyl-1H-pyrazole-3-carboxylate

The title compound was prepared as described in Example 1 Step 5 withmethyl1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-3-carboxylatereplacing methyl 4-(bromomethyl)benzoate.

¹H NMR (400 MHz, CDCl3): δ 7.37-7.21 (m, 7H); 6.92 (d, J=7.7 Hz, 1H);6.87-6.81 (m, 3H); 5.88 (s, 1H); 5.25-4.98 (m, 1H); 5.00 (s, 2H);4.05-3.91 (m, 3H); 3.92 (s, 3H); 1.44 (s, 9H).

Step 3: Methyl1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylate

The title compound was prepared as described in Example 1 Step 6 with(S)-methyl5-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)methyl)-1-methyl-1H-pyrazole-3-carboxylatereplacing methyl4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)methyl)benzoateand the product from this step used in Example 1 Step 7.

Step 4:1-Methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylicacid

The title compound was prepared as described in Example 1 Step 8 withmethyl1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)-1H-pyrazole-3-carboxylatereplacing4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate.

Step 5: 3-(1,3-Dioxolan-2-yl)propyl1-methyl-5((3((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylate

The title compound was prepared as described in Example 1 Step 10 with1-methyl-5((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)-1H-pyrazole-3-carboxylicacid and 3(1,3-dioxolan-2-yl)propan-1-ol replacing4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-benzoicacid and 4-(2-hydroxyethoxy)-3-methylbenzaldehyde respectively.

Step 6:4-(((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)butyl1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylate(Compound 36)

The title compound was prepared as described in Example 2 Step 6 andStep 7.

¹H NMR (400 MHz, DMSO-d₆): δ 8.48-8.07 (m, 3H); 8.18 (d, J=9.93 Hz, 1H);7.33-7.19 (m, 6H); 7.13-7.04 (m, 2H); 7.00-6.90 (m, 3H); 6.88 (s, 1H);6.51 (d, J=9.86 Hz, 1H); 5.83 (d, J=8.56 Hz, 1H); 5.32-5.03 (m, 3H);4.60 (s, 2H); 4.26-4.19 (m, 2H); 4.10-3.66 (m, 3H); 3.20-3.08 (m, 1H);2.93-2.54 (m, 9H); 2.06-1.28 (m, 8H).

The following compounds were prepared as described in Example 4 with theappropriate alkylating agent in Step 1 (methyl1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-3-carboxylate inthe case of Compound 36) used in Step 2 and the product used in thesubsequent steps in Example 4.

Compound Appropriate number alkylating agent Structure 37

38

Example 5(R)-Quinuclidin-3-yl((S)-(3-((3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate(Compound 39)

Step 1:(R)-Quinuclidin-3-yl((S)-(3-((3-((4,4-diethoxybutyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate

To a stirred solution of1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylicacid (0.30 g, 0.61 mmol) in DMF (6 mL) was added triethylamine (0.2 mL,1.53 mmol), 4-aminobutyraldehyde diethyl acetal (0.20 mL, 1.22 mmol),EDCI (0.18 g, 0.91 mmol) and 2-hydroxypyridine-N-oxide (0.09 g, 0.91mmol). The reaction mixture stirred at RT for 90 h. The reaction mixturewas diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate, brine, dried (magnesium sulfate), filtered and the solventevaporated at reduced pressure to afford the crude target material (0.22g, 57%) which was used directly without further purification.

Step 2:(R)-Quinuclidin-3-yl((S)-(3-((3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate(Compound 39)

The title compound was prepared as described in Example 2 Step 6 andStep 7.

¹H NMR (400 MHz, DMSO-d₆): δ 10.30 (br s, 1H); 8.48-8.07 (m, 3H);8.21-8.10 (m, 2H); 7.34-7.19 (m, 6H); 7.15-7.04 (m, 2H); 7.00-6.91 (m,2H); 6.75 (s, 1H); 6.53 (d, J=9.86 Hz, 1H); 5.84 (d, J=8.57 Hz, 1H);5.31-5.10 (m, 3H); 4.61 (s, 1H); 3.88 (s, 3H); 3.31-2.97 (m, 3H);2.95-2.56 (m, 7H); 1.94 (s, 1H); 1.82 (s, 1H); 1.73-1.16 (m, 9H).

The following compounds were prepared as described in Example 5 with theappropriate amine used in Step 1.

Compound number Appropriate amine Structure 39A

39B

39C

39D

Example 6(R)-Quinuclidin-3-yl((5)-(3-((5-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)furan-2-yl)methoxy)-phenyl)(phenyl)methyl)carbamate(Compound 40)

Step 1:5-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)furan-2-carboxylicacid

The title compound was prepared as described in Example 4 Step 2 withmethyl 5-(bromomethyl)furan-2-carboxylate replacing methyl1-methyl-5-(((methylsulfonyl)-oxy)methyl)-1H-pyrazole-3-carboxylatefollowed by the method of Example 4 Step 3. The crude product was usedin the next step without further purification.

Step 2:(R)-Quinuclidin-3-yl((S)-(3-((5-((4,4-diethoxybutyl)carbamoyl)furan-2-yl)methoxy)phenyl)(phenyl)methyl)carbamate

The title compound was prepared as described in Example 5 Step 1 with5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)furan-2-carboxylicacid replacing1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylicacid. The crude reaction product was used in the next step withoutfurther purification.

Step 3:(R)-Quinuclidin-3-yl((S)-(3-((5-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)furan-2-yl)methoxy)phenyl)-(phenyl)methyl)carbamate(Compound 40)

The title compound was prepared as described in Example 5 Step 2.

¹H NMR (400 MHz, DMSO-d₆): δ 10.38 (br s, 1H); 8.46-8.39 (m, 1H);8.33-8.21 (m, 3H); 8.18 (d, J=9.93 Hz, 1H); 7.34-7.19 (m, 6H); 7.11 (d,J=8.15 Hz, 1H); 7.05 (t, J=3.66 Hz, 2H); 6.99-6.89 (m, 3H); 6.69 (d,J=3.44 Hz, 1H); 6.54 (d, J=9.86 Hz, 1H); 5.84 (d, J=8.95 Hz, 1H); 5.20(dd, J=8.44, 4.14 Hz, 1H); 5.08 (s, 2H); 4.60 (s, 1H); 3.28-3.01 (m,3H); 2.88 (d, J=8.88 Hz, 2H); 2.79 (s, 6H); 1.93 (s, 1H); 1.88-1.73 (m,1H); 1.74-1.15 (m, 7H).

The following compounds were prepared as described in Example 6 with therequisite amine used in Step 2.

Compound Appropriate number amine Structure 40A

Example 7(R)-Quinuclidin-3-yl((S)-(3-((4-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)oxazol-2-yl)methoxy)phenyl)(phenyl)methyl)carbamate(Compound 41)

Step 1:2-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)oxazole-4-carboxylicacid

The title compound was prepared as described in Example 4 Step 2 withmethyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate replacing methyl1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-3-carboxylatefollowed by the method of Example 4 Step 3. The crude product was usedin the next step without further purification.

Step 2:(R)-Quinuclidin-3-yl((S)-(3-((4-((4,4-diethoxybutyl)carbamoyl)oxazol-2-yl)methoxy)phenyl)(phenyl)methyl)carbamate

The title compound was prepared as described in Example 5 Step 1 with2-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)oxazole-4-carboxylicacid replacing1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylicacid. The crude reaction product was used in the next step withoutfurther purification.

Step 3:(R)-Quinuclidin-3-yl((S)-(3-((4-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)oxazol-2-yl)methoxy)phenyl)-(phenyl)methyl)carbamate

The title compound was prepared as described in Example 5 Step 2.

¹H NMR (400 MHz, DMSO-d₆): δ 10.31 (br s, 1H); 8.61 (s, 1H); 8.37 (t,J=6.01 Hz, 1H); 8.37-8.17 (m, 2H); 8.17 (d, J=9.92 Hz, 1H); 7.33-7.19(m, 6H); 7.10 (d, J=8.15 Hz, 1H); 7.05-6.86 (m, 4H); 6.53 (d, J=9.86 Hz,1H); 5.83 (d, J=8.65 Hz, 1H); 5.25-5.14 (m, 3H); 4.59 (s, 1H); 3.23 (d,J=6.27 Hz, 2H); 3.21-3.06 (m, 1H); 2.86-2.52 (m, 8H); 1.92 (s, 1H); 1.80(s, 1H); 1.71-1.16 (m, 8H).

The following compounds were prepared as described in Example 5 with theappropriate acid used in Step 1.

Compound number Appropriate acid 41A

41B

41C

Compound number Structure 41A

41B

41C

Example 8(R)-3-((S)-(3-((5-((4-((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)butoxy)carbonyl)furan-2-yl)methoxy)phenyl)-(phenyl)methylcarbamoyloxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octanechloride hydrochloride (Compound 42) Step 1:5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)-methyl)furan-2-carboxylicacid hydrochloride

The5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)-methyl)furan-2-carboxylicacid prepared as described in Example 6 Step 1 was further purified byreverse phase column chromatography eluting with gradient of Eluent A:Water/ACN 95/5+0.1% HCOOH and Eluent B: ACN/water 95/5+0.1% HCOOH.5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylicacid formate (1:1) (8.36 g, 16.12 mmol) was dispersed in Dioxane (50 mL)and then 4M HCl in dioxane (16.12 mL, 64.5 mmol) was added at 0° C. andthe mixture stirred at rt for 10 minutes until complete dissolution. Theabove mentioned solution was dropped in a 500 mL of Et₂O under vigorousstirring to give a white precipitate that was collected by filtration.After drying under vacuum5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylicacid hydrochloride (8.2 g, 15.98 mmol, 99% yield) was isolate as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.90-13.34 (bs, 1H), 10.10 (bs, 1H),8.43 (d, J=9.26 Hz, 1H), 7.13-7.42 (m, 7H), 7.04 (m., 1H), 6.86-7.00 (m,2H), 6.72 (d, J=3.53 Hz, 1H), 5.83 (d, J=9.26 Hz, 1H), 5.11 (s, 2H),4.61-4.95 (m, 1H), 3.57-3.75 (m, 1H), 2.95-3.27 (m, 5H), 2.22 (m, 1H),1.65-2.10 (m, 4H)

Step 2:4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)butyl5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylate

5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)-methyl)furan-2-carboxylicacid hydrochloride (3.09 g, 6.03 mmol) and (R)-tert-butyl2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl(4-hydroxybutyl)carbamate(see Preparation of(R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-onehydrochloride, Step 3) (3 g, 5.03 mmol) were dissolved in 15 mL of DMF,then EDC (1.445 g, 7.54 mmol) was added and the mixture cooled at 0° C.DMAP (0.307 g, 2.51 mmol) dissolved in 7 mL of DMF was added dropwise at0° C. and the mixture was stirred 5 minutes at 0° C., 30 min at rt andheated at 50° C. for 3 hours and then left overnight at rt. Reaction wasthen partitioned between AcOEt (300 mL) and brine (600 mL). The organiclayer was washed twice with 1:1 mixture water/brine (2×300 mL). Organicphase was washed with brine (300 mL), dried over Na₂SO₄ and evaporatedto give a white foam. The foam was triturated in 300 mL of 95/5Hexane/AcOEt for 3 hours and the precipitate was collected byfiltration. A second crop was obtained by dilution with hexane of themother liquor.4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)butyl5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylate(4.3 g from the 2 crops reunited, 4.07 mmol, 81% yield) was obtained asa white powder.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.64 (bs, 1H), 8.32 (d, J=8.82 Hz, 2H),7.57 (d, J=7.50 Hz, 2H), 7.12-7.44 (m, 11H), 6.85-7.08 (m, 3H), 6.73 (d,J=2.65 Hz, 1H), 6.47-6.64 (m, 1H), 5.82 (d, J=8.82 Hz, 1H), 5.31 (s,2H), 5.10 (s, 2H), 4.65-4.78 (m, 1H), 4.21 (t, 2H), 2.73-3.27 (m, 10H),1.46-2.18 (m, 9H), 1.37 (s, 9H), 0.81 (s, 9H), −0.01 (s, 3H), −0.20 (s,3H)

Step 3:4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)butyl5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylate formate

4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl)(tert-butoxycarbonyl)amino)butyl5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylate(2.1 g, 1.990 mmol), 10% Pd/C (0.106 g, 0.099 mmol) and formic acid(0.092 mL, 2.388 mmol) were dissolved in MeOH (44.2 mL) and stirred atRT under balloon pressure of H₂. After 2 hours reaction was complete andit was filtered on a pad of celite and the filtrate concentrated underreduced pressure to give a colourless viscous oil. The oil was dispersedin Et₂O/AcOEt and evaporated 3 times in order to obtain a heavy whitefoam that was triturated in hexane/Et₂O/AcOEt to give a white solid thatwas collected by filtration. The mother liquor was concentrated to give0.44 g of a second crop of a whitish foam. The 2 crops were reunited togive4-(tert-butoxycarbonyl((R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)-methyl)furan-2-carboxylateformate (1.95 g, 1.928 mmol, 97% yield) as white amorphous solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.38 (br. s., 2H), 8.33 (br. s., 2H),8.14 (s, 1H), 7.16-7.40 (m, 7H), 6.84-7.06 (m, 5H), 6.73 (m, 1H),6.41-6.60 (m, 1H), 5.82 (d, J=9.26 Hz, 1H), 5.18-5.50 (m, 1H), 5.10 (s,2H), 4.63-4.82 (m, 1H), 4.20 (t, J=5.95 Hz, 2H), 2.71-3.22 (m, 10H),1.44-2.16 (m, 9H), 1.44 (s, 9H), 0.80 (s, 9H), −0.01 (s, 3H), −0.19 (s,3H)

Step 4:4-(tert-butoxycarbonyl((R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylatechloride hydrochloride

4-(tert-butoxycarbonyl((R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl5-((3-((S)-phenyl(((R)-quinuclidin-3-yloxy)carbonylamino)methyl)phenoxy)methyl)furan-2-carboxylateformate (150 mg, 0.148 mmol) was dissolved in 500 uL of dioxane and thena solution of 2-bromo-1-(thiophen-2-yl)ethanone (33.5 mg, 0.163 mmol) in0.3 mL of dioxane was added. After 2 hours a second eq. of alkylatingagent was added and the mixture stirred at RT overnight. To drive thereaction to completion sodium bicarbonate (33 mg, 0.393 mmol) was addedand the reaction mixture was the heated at 50° C. for 6 hours. Thereaction was cooled at RT and then Et₂O was added. The precipitate wascollected as gummy solid dissolved in MeOH and evaporated to give ayellow residue that was dissolved in 2-propanol (1.8 ml). HCl in Dioxane(1.859 ml, 7.43 mmol) was added and the mixture stirred at RT overnight.The reaction mixture was diluted with Et₂O and the precipitate formedwas collected by filtration and purified by reverse phase columnchromatography eluting with ACN:Water (gradient from 100% to 40% of ACNleading to(R)-3-((S)-(3-((5-((4-((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)butoxy)carbonyl)furan-2-yl)methoxy)phenyl)(phenyl)-methylcarbamoyloxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octanechloride hydrochloride (96 mg, 0.101 mmol, 68.1% yield) as pale yellowsolid obtained by mean of trituration with EtOH and Et₂O of the residue.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.87-10.55 (bs, 1H), 8.52 (d, J=9.26 Hz,1H), 8.33 (s, 2H), 8.11-8.20 (m, 2H), 8.05 (d, J=3.53 Hz, 1H), 7.17-7.46(m, 7H), 6.87-7.10 (m, 5H), 6.74 (d, J=3.53 Hz, 1H), 6.48 (d, J=9.70 Hz,1H), 5.84 (d, J=9.26 Hz, 1H), 4.93-5.23 (m, 6H), 4.23 (t, J=6.39 Hz,2H), 3.98-4.12 (m, 2H), 3.52-3.75 (m, 4H), 2.57-2.80 (m, 4H), 2.32 (m,1H), 1.86-2.23 (m, 4H), 1.60-1.77 (m, 2H), 1.44-1.57 (m, 2H)

Example 9(R)-Quinuclidin-3-yl((S)-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate(Compound 43)

Step 1: (4-(1,3-Dioxolan-2-yl)phenyl)methanamine

To a stirred solution of 4-cyanobenzaldehyde (1.31 g, 10.0 mmol) and4-toluenesulfonic acid hydrate (0.19 g, 1.0 mmol) in toluene (30 mL) wasadded ethylene glycol (2.30 mL, 41.2 mmol). The reaction mixture washeated at reflux under Dean and Stark conditions for 3 hours. Thereaction mixture was diluted with ethyl acetate and washed with water,10% aqueous potassium carbonate solution and brine. The organic phasewas dried (magnesium sulfate), filtered and the solvent evaporated atreduced pressure. The residue was dissolved in anhydrous THF (10 mL) andadded dropwise to an ice-cooled solution of lithium aluminium hydride inTHF (2M in THF, 15.0 mL, 30.0 mmol). The reaction mixture was allowed towarm to room temperature at stirred at this temperature for 18 hours.Water (1.2 mL), 2M aqueous sodium hydroxide (1.2 mL) and water (3.6 mL)were added sequentially and the subsequent mixture stirred at roomtemperature for 30 minutes. Ethyl acetate and magnesium sulfate addedand the mixture stirred for a further 30 minutes. The reaction mixturewas filtered and the filtrate evaporated at reduced pressure to affordthe title compound (1.56 g, 87%).

¹H NMR (400 MHz, CDCl₃): δ 7.46 (m, 2H); 7.34 (d, J=8.4 Hz, 2H); 5.81(s, 1H); 4.17-4.00 (m, 2H); 3.88 (s, 2H); 1.55 (s, 2H).

Step 2: (S)-Methyl4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate

A mixture of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate(3.20 g, 10.7 mmol), methyl 4-(bromomethyl)benzoate (2.70 g, 11.8 mmol)and potassium carbonate (2.20 g, 16.1 mmol) in acetonitrile (54 mL) wasstirred at RT for 16 hours. The reaction mixture was concentrated atreduced pressure and the residue partitioned between ethyl acetate andwater. The aqueous phase was extracted with further ethyl acetate andthe combined organic extracts combined, dried with anhydrous magnesiumsulfate, filtered and the solvent evaporated at reduced pressure. Theresidue was recrystallised from ethyl acetate and iso-hexane to affordthe title compound as a white solid (3.25 g, 68%).

¹H NMR (400 MHz, CDCl3): δ 8.04 (d, J=8.2 Hz, 2H); 7.46 (d, J=8.2 Hz,2H); 7.34-7.20 (m, 6H); 6.90-6.81 (m, 3H); 5.87 (s, 1H); 5.13 (s, 1H);5.07 (s, 2H); 3.92 (s, 3H); 1.44 (s, 9H).

Step 3: (S)-Methyl 4-((3-(amino(phenyl)methyl)phenoxy)methyl)benzoatehydrochloride

To a solution of methyl4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate(3.21 g, 7.20 mmol) in methanol (36 mL) was added hydrogen chloride indioxane (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at RTfor 16 hours. The solvent was removed at reduced pressure to afford thetitle compound (2.65 g, >95%).

¹H NMR (400 MHz, CDCl3): δ 9.21 (s, 2H); 8.03 (d, J=8.1 Hz, 2H); 7.64(d, J=8.1 Hz, 2H); 7.59 (d, J=7.6 Hz, 2H); 7.49-7.34 (m, 5H); 7.17 (d,J=7.7 Hz, 1H); 7.06 (dd, J=8.3, 2.4 Hz, 1H); 5.64 (s, 1H); 5.28 (s, 2H);3.91 (s, 3H).

Step 4: Methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate

To a stirred solution of (S)-methyl4-((3-(amino(phenyl)methyl)phenoxy)-methyl)benzoate hydrochloride (12.0g, 31.3 mmol) in pyridine (100 mL) at 0° C. was added portion-wise(R)-quinuclidin-3-yl carbonochloridate (8.50 g, 37.5 mmol). The reactionwas stirred at 0° C. for 1 hour and then allowed to warm to RT for 16hours. Water was added to the reaction mixture and extracted with ethylacetate (×3). The combined extracts were washed with brine, dried(sodium sulfate), filtered and the solvent evaporated at reducedpressure. The crude material was purified by chromatography on a KP-NHBiotage cartridge eluting with 0-20% methanol in ethyl acetate to affordthe title compound (10.3 g, 66%).

Step 5:4-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoicacid

To a stirred solution of methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate(2.27 g, 4.50 mmol) in THF (23 mL) was added an aqueous solution oflithium hydroxide (2.0 M, 9.0 ml, 18.0 mmol). The mixture was stirred atRT for 16 hours. The pH of the reaction mixture was adjusted to 6 by theaddition of 4M aqueous hydrochloric acid. The mixture was then extractedwith 10% methanolic ethyl acetate (×2) and the combined organic extractsevaporated at reduced pressure. The residue was then dissolved inethanol and re-evaporated at reduced pressure to afford the titlecompound as a pale yellow solid (1.85 g, 84%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J=9.4 Hz, 1H); 7.99 (d, J=7.9 Hz,2H); 7.58 (d, J=8.0 Hz, 2H); 7.42-7.26 (m, 6H); 7.09 (s, 1H); 7.02-6.91(m, 2H); 5.87 (d, J=9 Hz, 1H); 5.21 (s, 2H); 4.76 (s, 1H); 3.98-2.72 (m,6H); 2.12-1.54 (m, 5H).

Step 6:(R)-Quinuclidin-3-yl((S)-(3-((4-((4-(1,3-dioxolan-2-yl)benzyl)carbamoyl)-benzyl)oxy)phenyl)(phenyl)methyl)carbamate

The title was prepared as described in Example 5 Step 1 with4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoicacid and (4-(1,3-dioxolan-2-yl)phenyl)methanamine replacing1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-1H-pyrazole-3-carboxylicacid and 4-aminobutyraldehyde diethyl acetal respectively.

Step 7:(R)-Quinuclidin-3-yl((S)-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate(Compound 43)

The title compound was prepared as described in Example 3 Step 4 andStep 5 with(R)-quinuclidin-3-yl((S)-(3-((4-((4-(1,3-dioxolan-2-yl)benzyl)carbamoyl)benzyl)-oxy)phenyl)(phenyl)methyl)carbamatereplacing 3-(1,3-dioxolan-2-yl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoateand the product used in Step 5.

¹H NMR (400 MHz, DMSO-d₆): δ 9.06-9.00 (m, 1H); 8.31-8.23 (m, 3H); 8.12(d, J=9.9 Hz, 1H); 7.90 (d, J=8.1 Hz, 2H); 7.52 (d, J=8.0 Hz, 2H);7.32-7.17 (m, 10H); 7.05 (t, J=4.2 Hz, 2H); 6.96-6.85 (m, 3H); 6.53-6.45(m, 1H); 5.82 (d, J=9.2 Hz, 1H); 5.18-5.06 (m, 3H); 4.62 (s, 2H); 4.47(d, J=5.9 Hz, 2H); 3.92-3.68 (m, 2H); 2.88-2.51 (m, 7H); 1.95 (s, 1H);1.83 (s, 1H); 1.62 (s, 1H); 1.52 (s, 1H); 1.39 (s, 1H).

The following compounds were prepared as described in Example 9 with therequisite aldehyde used in Step 1.

Compound number Appropriate aldehyde Structure 41

The following compounds were prepared as described in Example 9 with therequisite halide used in Step 2 replacing methyl(4-bromomethyl)benzoateand the requisite amine used in Step 6 replacing(4-(1,3-dioxolan-2-yl)phenyl)methanamine.

Compound number Requisite halide Requisite amine 45

46

47

48

49

50

51

52

Compound number Structure 45

46

47

48

49

50

51

52

Synthesis of Compounds 53 to 55

Example 10(R)-Quinuclidin-3-yl((S)-(3-((5′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)(phenyl)methyl)carbamate(Compound 53)

Step 1:(R)-Quinuclidin-3-yl((S)-(3-((4-bromobenzyl)oxy)phenyl)(phenyl)-methyl)carbamate

The title compound was prepared as described in Example 1 Step 1 to Step7 with 4-bromobenzyl bromide replacing methyl 4-(bromomethyl)benzoate inStep 5.

¹H NMR (400 MHz, DMSO-d₆): δ 8.23 (d, J=9.2 Hz, 1H); 7.59-7.56 (m, 2H);7.40-7.38 (m, 2H); 7.32-7.22 (m, 6H); 7.01 (s, 1H); 6.95-6.86 (m, 2H);5.83 (d, J=9.2 Hz, 1H); 5.06 (s, 2H); 4.57-4.55 (m, 1H); 3.18 (m, 1H);2.72-2.47 (m, 5H); 1.89 (s, 1H); 1.78 (s, 1H); 1.58 (m, 1H); 1.46 (s,1H); 1.32 (s, 1H).

Step 2:(R)-Quinuclidin-3-yl((S)-(3-((5′-formyl-2′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)(phenyl)methyl)carbamate

To a solution of(R)-quinuclidin-3-yl((S)-(3-((4-bromobenzyl)oxy)phenyl)-(phenyl)methyl)carbamate(0.30 g, 0.57 mmol) and 5-formyl-2-methoxyphenyl boronic acid (0.15 g,0.86 mmol) in toluene/water (2 mL/0.5 mL) was added sodium carbonate(0.12 g, 1.14 mmol). Nitrogen was bubbled through the reaction mixturefor 5 minutes and then treated withtetrakis(triphenylphosphine)palladium (0) (0.03 g, 0.03 mmol) and thereaction mixture heated under reflux for 2 hours. The reaction mixturewas diluted with ethyl acetate and washed with water and brine. Theorganic phase was dried (magnesium sulfate), filtered and the solventevaporated at reduced pressure. The residue was loaded onto an SCX-2cartridge and eluted with acetonitrile (4 column volumes) and then 10%triethylamine/acetonitrile (4 column volumes).

The 10% triethylamine/acetonitrile fractions analyzed by TLC and productcontaining fractions combined and evaporated at reduced pressure.Material used directly in the next step with no further purification.

Step 3:(R)-Quinuclidin-3-yl((S)-(3-((5′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)(phenyl)methyl)carbamate(Compound 53)

The title compound was prepared as described in Example 1 Step 11 with(R)-quinuclidin-3-yl((S)-(3-((5′-formyl-2′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)-phenyl)(phenyl)methyl)carbamatereplacing 2-(4-formyl-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate.

¹H NMR (400 MHz, DMSO-d₆): δ 8.32-8.23 (m, 3H); 8.11 (d, J=9.9 Hz, 1H);7.63-7.33 (m, 4H); 7.35-7.21 (m, 8H); 7.09-7.04 (m, 3H); 6.96-6.88 (m,3H); 6.45 (d, J=9.9 Hz, 1H); 5.84 (d, J=9.1 Hz, 1H); 5.17-5.08 (m, 3H);4.66-4.59 (m, 1H); 3.83 (s, 2H); 3.76 (s, 3H); 3.23-3.12 (m, 1H);2.85-2.51 (m, 7H); 1.93 (s, 1H); 1.83 (s, 1H); 1.62 (s, 1H); 1.52 (s,1H); 1.39 (s, 1H).

The following compounds were prepared as described in Example 10 withthe requisite boronic acid used in Step 2 replacing5-formyl-2-methoxyphenyl boronic acid.

Compound Requisite boronic number acid Structure 54

55

Example 11(R)-Quinuclidin-3-yl((S)-(3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate(Compound 56)

Step 1: 4-(1,3-Dioxolan-2-yl)benzyl methanesulfonate

To an ice-cooled stirred solution of(4-(1,3-dioxolan-2-yl)phenyl)methanol (prepared as described inWO2012168359, which is incorporated herein by reference in its entirety,1.2 g, 6.6 mmol) and triethylamine (2.8 mL, 20.0 mmol) in DCM (40 mL)was added dropwise a solution of methanesulfonyl chloride (0.77 mL, 10.0mmol) in DCM (10 mL). The reaction mixture was stirred at thistemperature for 40 minutes and then at room temperature for 18 hours.The reaction mixture was washed with water and the organic phase dried(magnesium sulfate). The filtrate was evaporated at reduced pressure toafford the title compound which was used immediately without furtherpurification.

Step 2:(R)-Quinuclidin-3-yl((S)-(3-((4-(1,3-dioxolan-2-yl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate

The title compound was prepared as described in Example 1 Step 1 to Step7 with 4-(1,3-dioxolan-2-yl)benzyl methanesulfonate replacing methyl4-(bromomethyl)-benzoate. The product was used directly in the next stepwithout any purification.

Step 3:(R)-Quinuclidin-3-yl((S)-(3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate(Compound 56)

The title compound was prepared as described in Example 3 Step 4 andStep 5 with(R)-quinuclidin-3-yl((S)-(3-((4-(1,3-dioxolan-2-yl)benzyl)oxy)phenyl)(phenyl)-methyl)carbamatereplacing 3-(1,3-dioxolan-2-yl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoateand the product used in Step 5.

¹H NMR (400 MHz, DMSO-d₆): δ 8.31-8.20 (m, 3H); 8.11 (d, J=9.9 Hz, 1H);7.41-7.27 (m, 8H); 7.26-7.20 (m, 2H); 7.12-7.00 (m, 2H); 6.94-6.83 (m,3H); 6.48 (d, J 9.9 Hz, 1H); 5.82 (d, J=9.3 Hz, 1H); 5.10 (dd, J=8.0,4.5 Hz, 1H); 5.04 (s, 2H); 4.63-4.62 (m, 1H); 3.81 (s, 2H); 3.27-3.08(m, 1H); 2.82 (br s, 2H); 2.81-2.56 (m, 5H); 1.96 (br s, 1H); 1.90-1.84(m, 1H); 1.70-1.60 (m, 1H); 1.63-1.46 (m, 1H); 1.44-1.38 (m, 1H).

The following compounds were prepared as described in Example 11 withthe requisite alcohol used in Step 1 replacing(4-(1,3-dioxolan-2-yl)phenyl)methanol.

Compound number Requisite alcohol Structure 57

  Prepared as described in Collection of Czechoslovak ChemicalCommunications, 57(1), 159-68; 1992

58

  Prepared as described in PCT Int. Appl., 2012168359, 13 December 2012

59

  Prepared as described in PCT Int. Appl., 2004101767, 25 November 2004

60 Prepared as described in Example 3 Step 1 and Step 2 starting frommethyl 4- formyl nicotinate  

61 Prepared as described in Example 3 Step 1 and Step 2 starting frommethyl 4- formyl-3-methoxy- benzoate  

Example 12(R)-Quinuclidin-3-yl((S)-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)-amino)-2-oxoethoxy)phenyl)-(phenyl)methyl)carbamate(Compound 62)

Step 1:2-(3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)aceticacid

The title compound was prepared as described in Example 1 Step 1 to Step7 with methyl bromoacetate replacing methyl 4-(bromomethyl)benzoate inStep 5.

¹H NMR (400 MHz, DMSO-d₆): δ 8.32-8.24 (m, 1H); 7.34-7.12 (m, 6H); 6.89(s, 1H); 6.84 (d, J=7.6 Hz, 1H); 6.69 (dd, J=8.2, 2.5 Hz, 1H); 5.79 (d,J=9.2 Hz, 1H); 4.72-4.70 (m, 1H); 4.37 (s, 2H); 3.30-3.29 (m, 1H); 2.93(s, 2H); 2.89-2.69 (m, 4H); 2.05-2.03 (m, 1H); 1.92-1.88 (m, 1H);1.70-1.50 (m, 3H).

Step 2:(R)-Quinuclidin-3-yl((S)-(3-(2-((4-(hydroxymethyl)phenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate

The title compound was prepared as described in Example 1 Step 10 with2-(3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)aceticacid replacing4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid and 4-aminobenzyl alcohol replacing4-(2-hydroxyethoxy)-3-methylbenzaldehyde.

Step 3:(R)-Quinuclidin-3-yl((S)-(3-(2-((4-formylphenyl)amino)-2-oxoethoxy)phenyl)-(phenyl)methyl)carbamate

To a stirred solution of(R)-quinuclidin-3-yl((S)-(3-(2-((4-(hydroxymethyl)-phenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate(0.68 g, 1.31 mmol) in 1,4-dioxane (10 mL) was added manganese (IV)oxide (0.57 g, 6.58 mmol). The reaction mixture was stirred at roomtemperature for 60 hours. The suspension was filtered and the filtercake was washed with ethyl acetate. The filtrate was evaporated atreduced pressure to afford the crude title compound. This material wasused without further purification.

Step 4:(R)-Quinuclidin-3-yl((S)-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)amino)-2-oxoethoxy)phenyl)-(phenyl)methyl)carbamate(Compound 62)

The title compound was prepared as described in Example 11 Step 11.

¹H NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 1H); 10.23 (s, 1H); 9.63 (s, 1H);9.05 (s, 1H); 8.48 (d, J=9.2 Hz, 1H); 8.06 (d, J=9.9 Hz, 1H); 7.66 (d,J=8.2 Hz, 2H); 7.47 (d, J=8.4 Hz, 2H); 7.36-7.17 (m, 7H); 7.12 (d, J=8.2Hz, 1H); 7.05-6.95 (m, 3H); 6.87 (dd, J=8.3, 2.5 Hz, 1H); 6.56 (d, J=9.9Hz, 1H); 6.18 (s, 1H); 5.86-5.81 (m, 1 H); 5.32 (d, J=9.6 Hz, 1H);4.89-4.84 (m, 1H); 4.69 (s, 2H); 4.19 (s, 2H); 3.71-3.60 (m, 1H);3.30-2.90 (m, 7H); 2.24 (s, 1H); 2.10-1.70 (m, 4H).

The following compounds were prepared as described in Example 12 withthe requisite amine used in Step 2 in place of 4-aminobenzyl alcohol.

Compound number Requisite amine Structure 63

64

65

Example 13(R)-Quinuclidin-3-yl((S)-(3-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)-3-(trifluoromethyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate(Compound 66)

Step 1:(R)-Quinuclidin-3-yl((S)-(3-((4-bromo-3-(trifluoromethyl)benzyl)oxy)-phenyl)(phenyl)methyl)carbamate

The title compound was prepared as described in Example 1 Step 1 to Step7 with 4-bromo-3-trifluoromethyl-benzyl bromide replacing methyl4-(bromomethyl)benzoate in Step 5.

¹H NMR (400 MHz, DMSO-d₆): δ 8.22 (d, J=9.6 Hz, 1H); 7.90 (d, J=7.0 Hz,2H); 7.65 (d, J=8.3 Hz, 1H); 7.32-7.18 (m, 6H); 7.04 (s, 1H); 6.97 (d,J=7.7 Hz, 1H); 6.90 (dd, J=8.2, 2.5 Hz, 1H); 5.83 (d, J=9.5 Hz, 1H);5.16 (s, 2H); 4.56 (s, 1H); 3.07 (t, J=10.7 Hz, 1H); 2.79-2.54 (m, 5H);1.89 (s, 1H); 1.78 (s, 1H); 1.57 (s, 1H); 1.46 (s, 1H); 1.32 (s, 1H).

Step 2:(R)-quinuclidin-3-yl((S)-(3-((4-((E)-2-ethoxyvinyl)-3-(trifluoromethyl)-benzyl)oxy)phenyl)(phenyl)methyl)carbamate

To a mixture of(R)-quinuclidin-3-yl((S)-(3-((4-bromo-3-(trifluoromethyl)-benzyl)oxy)phenyl)(phenyl)methyl)carbamate(0.295 g, 0.50 mmol) and cesium carbonate (0.494 g, 1.50 mmol) was addeddegassed 1,4-dioxane/water (4/1, 5 mL). This mixture was treated with2-ethoxyethylenyl-1-boronic acid pinacol ester (0.152 g, 0.75 mmol) andthe mixture de-gassed with nitrogen.Tetrakis(triphenylphosphine)palladium (0) (0.029 g, 0.025 mmol) wasadded and the reaction mixture heated at reflux for 3 hours. Thereaction mixture was evaporated at reduced pressure and the residuepartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried (magnesium sulfate), filtered and the solventevaporated at reduced pressure. The crude material was purified bychromatography eluting with 0-20% methanol in ethyl acetate to affordthe title compound (0.258 g, 89%).

¹H NMR (400 MHz, DMSO-d₆): δ 8.23 (d, J=9.5 Hz, 1H); 7.70 (d, J=8.9 Hz,2H); 7.67-7.55 (m, 1H); 7.34-7.20 (m, 6H); 7.05 (s, 1H); 6.97-6.85 (m,2H); 5.98 (dd, J=12.6, 2.6 Hz, 1H); 5.82 (d, J=9.5 Hz, 1H); 5.11 (s,2H); 4.56 (s, 1H); 3.95 (q, J=7.0 Hz, 2H); 3.07 (t, J=10.8 Hz, 1H);2.2.81-2.48 (m, 6H); 1.89 (s, 1H); 1.79 (s, 1H); 1.57 (s, 1H); 1.45 (s,1H); 1.28 (t, J=7.0 Hz, 4H).

Step 3:(R)-Quinuclidin-3-yl((S)-(3-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)-3-(trifluoromethyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate(Compound 66)

The title compound was prepared as described in Example 3 Step 4 andStep 5 with(R)-quinuclidin-3-yl((S)-(3-((4-((E)-2-ethoxyvinyl)-3-(trifluoromethyl)benzyl)oxy)-phenyl)(phenyl)methyl)carbamatereplacing 3-(1,3-dioxolan-2-yl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoateand the product used in Step 5.

¹H NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 2H); 9.67 (s, 1H); 8.94 (br s,2H); 8.46 (d, J=9.25 Hz, 1H); 8.18 (d, J=9.95 Hz, 1H); 7.80 (s, 1H);7.73 (d, J=8.06 Hz, 1H); 7.55 (d, J=8.00 Hz, 1H); 7.33-7.21 (m, 6H);7.17 (d, J=8.19 Hz, 1H); 7.05-6.97 (m, 3H); 6.91 (dd, J=8.27, 2.41 Hz,1H); 6.59 (m, 2H); 6.24 (s, 1H); 5.84 (d, J=9.09 Hz, 1H); 5.35 (d,J=9.65 Hz, 1H); 5.15 (s, 2H); 4.88-4.83 (m, 1H); 3.72-3.60 (m, 1H);3.27-3.11 (m, 10H); 2.23 (br s, 1H); 2.13-1.99 (m, 1H); 1.96-1.68 (m,3H).

The following compounds were prepared as described in Example 13 withthe requisite benzyl bromide used in Step 1 in place of4-bromo-3-trifluoromethyl-benzyl bromide.

Compound Requisite benzyl number bromide Structure 67

68

Large scale synthesis of (S)-3-(amino(phenyl)methyl)phenol hydrochloride

Step 1: (3-Methoxyphenyl)(phenyl)methanone

To the mixture of phosphorus pentachloride (3763 g, 18.1 mol) in 7500 mLof benzene, 3-methoxy benzoic acid (2500 g, 16.4 mol) was added inportions. The mixture was stirred for 50 minutes until it becamehomogenous. The formation of the acid chloride was controlled by TLC.After completion, the mixture was cooled down to 10° C., reactor wascovered with aluminum foil and aluminium trichloride (4820 g, 36.1 mol)was added in portions (internal temperature was held up to 30° C.maximum). Stirring was continued for 18 hours at RT. The reaction wasmonitored by TLC (AcOEt:hex 1:9). After completion, the reaction mixturewas poured into ice and was diluted with AcOEt (7 L). Then organic layerwas separated and the aqueous layer was extracted with AcOEt (2×10 L,1×6 L). Combined organic layers were washed with water (5×3 L) topH˜6-7, saturated aqueous sodium hydrogen carbonate solution (15 L),dried (sodium sulfate), filtered and the solvent evaporated at reducedpressure to give a crude oil. The product was purified by vacuumdistillation (130-139° C., 2 mbar) to obtain title compound as a (2637 g76%) of pale yellow oil.

¹H NMR (600 MHz, CDCl₃); δ 7.80 (m, 2H); 7.57 (m, 1H); 7.46 (m, 2H);7.32-7.37 (m, 3H); 7.12 (m, 1H); 3.83 (s, 3H).

Step 2: (3-Hydroxyphenyl)(phenyl)methanone

1458 g (6.9 mol) of (3-methoxyphenyl)(phenyl)methanone was dissolved in2090 mL of AcOH. To the solution, 2320 ml (20.6 mol) of 48% HBr wasadded and the mixture was stirred at 90° C. for 18 hours. The reactionwas monitored by TLC (AcOEt:hex 1:9). After reaction was completed themixture was cooled down to RT and poured into ice with stirring. Theprecipitated solid was filtered, washed with water and dried yieldingthe title compound as a white solid (1234 g, 91%).

¹H NMR (600 MHz, CDCl₃); δ 7.80 (m, 2H); 7.58 (m, 1H); 7.47 (m, 2H);7.39 (m, 1H); 7.28-7.34 (m, 2H); 7.11 (m, 1H); 5.59 (brs, 1H).

Step 3: 3-(Amino(phenyl)methyl)phenol

(3-Hydroxyphenyl)(phenyl)methanone (400 g, 2 mol) was dissolved inmethanol (4 L). Hydroxylamine hydrochloride (168 g, 2.4 mol) and sodiumacetate (331 g, 4 mol) were added to the resulting solution. The mixturewas heated at reflux for 18 hours. After cooling to RT solvent wasevaporated at reduced pressure, then water (3 L) was added to theresidue. The product was extracted with ethyl acetate (3×3 L). Thecombined organic extracts were washed with saturated aqueous sodiumhydrogen carbonate, brine, dried (sodium sulfate), filtered and thesolvent evaporated at reduced pressure. The crude residue (1085 g) wasused in the next step without purification. The crude oxime, 362 g, (287g, 1.3 mol of pure oxime based on analysis) was dissolved in ethanol(860 mL) and 25% aqueous ammonia (3000 mL). To this mixture ammoniumacetate (52 g, 0.7 mol) was added followed by portion wise addition ofzinc powder (440 g, 6.7 mol) to maintain an internal not exceeding 40°C. The mixture was stirred without heating for 18 hours then filteredthrough a pad of celite. The filter cake was washed with ethyl acetate.The filtrate was collected and the formed layers were separated. Theaqueous layer was extracted with ethyl acetate (5×5 L). The combinedorganic extracts layers were washed with brine (×2) and the solvent wasevaporated at reduced pressure. The product was dried in vacuo (35° C.,18 hours).

¹H NMR (600 MHz, DMSO-d₆); δ 9.25 (brs, 1H); 7.36 (m, 2H); 7.25 (m, 2H);7.15 (m, 1H); 7.03 (m, 1H); 6.79 (m, 2H); 6.54 (m, 1H); 4.98 (s, 1H);2.17 (brs, 2H).

Step 4: Crystallization of (S)-3-(amino(phenyl)methyl)phenol(S)-mandelate

Salt formation: 3-(Amino(phenyl)methyl)phenol (1081 g, 5.4 mol) wasdissolved in iso-propanol (21.62 L) and heated to reflux. To the mixturea solution of S-mandelic acid (908 g, 6 mol) in iso-propanol (2160 mL)was added dropwise. The mixture was heated at reflux for 1 hour and thenallowed to cool to 10° C. (over 18 hours). The precipitate formed wasfiltered, washed with cold iso-propanol and dried n vacuo at 35° C. Theobtained salt was refluxed in 95% iso-propanol for 1 hour. The mixturewas allowed to cool down to 10° C. over 18 hours. The solid wasfiltered, washed with cold iso-propanol and dried in vacuum oven at 35°C. The crystallization process was repeated two or more times until theee was >98% by chiral HPLC analysis.

Step 5: (S)-3-(Amino(phenyl)methyl)phenol hydrochloride

(S)-3-(Amino(phenyl)methyl)phenol (S)-mandelate (1027 g, 2.9 mol) of wassuspended in ethyl acetate. A solution of sodium hydrogen carbonate (737g, 8.8 mol) in water (11.05 L) was added drop wise and the mixture wasstirred at RT for 18 hours. The mixture was separated and aqueous layerwas extracted with ethyl acetate (5×10 L). The combined organic extractswere combined and the solvent evaporated at reduced pressure to give 464g (85%) of amine as a pale yellow crystals.

The amine (464 g, 2.3 mol) was suspended in methanol and 4M HCl in AcOEt(3500 mL, 14 mol) was added drop wise. The mixture was stirred for 18hours and the solvent evaporated at reduced pressure. The residue wastriturated with ether (2740 mL) for 18 hours. The suspension wasfiltered, the filter cake washed with ether and dried.

¹H NMR (600 MHz, DMSO-d₆); δ 9.74 (s, 1H); 9.19 (s, 3H); 7.54 (m, 2H);7.40 (m, 2H); 7.33 (m, 1H); 7.19 (m, 1H); 7.00 (m, 1H); 6.89 (m, 1H);6.78 (m, 1H); 5.49 (s, 1H, CH).

LCMS/HPLC Cpd. method NMR data at 400 MHz Salt 1 A (DMSO-d₆): δ8.29-8.20 (m, 2 H); Formate 8.10 (d, J = 9.9 Hz, 1 H); 7.97 (d, J = 8.0Hz, 2 H); 7.57 (d, J = 8.0 Hz, 2 H); 7.32-7.18 (m, 6 H); 7.17-7.01 (m, 4H); 6.98-6.85 (m, 4 H); 6.47 (d, J = 9.9 Hz, 1 H); 5.81 (s, 1 H); 5.17(s, 2 H); 5.09 (dd, J = 7.9, 4.7 Hz, 1 H); 4.60 (d, J = 16.8 Hz, 3 H);4.31 (d, J = 5.0 Hz, 2 H); 3.71 (s, 2 H); 3.12 (m, 1 H); 2.81-2.52 (m, 6H); 2.09 (s, 4 H); 1.92 (s, 1 H); 1.69-1.26 (m, 4 H). 2 C (DMSO-d₆): δ10.31 (br s, 1 H); Formate 8.26-8.19 (m, 2 H); 8.10 (d, J = 9.92 Hz, 1H); 7.96 (d, J = 8.07 Hz, 2 H); 7.56 (d, J = 8.01 Hz, 2 H); 7.31-7.16(m, 8 H); 7.07-7.00 (m, 2 H); 6.97-6.85 (m, 5 H); 6.47 (d, J = 9.86 Hz,1 H); 5.81 (d, J = 9.03 Hz, 1 H); 5.17 (s, 2 H); 5.06 (dd, J = 7.90,4.39 Hz, 1 H); 4.62-4.58 (m, 3 H); 4.34-4.29 (m, 2 H); 3.70 (s, 2 H);3.16-3.04 (m, 1 H); 2.75-2.57 (m, 5 H); 2.34-2.31 (m, 1 H); 1.94-1.74(m, 2 H); 1.64-1.28 (m, 4 H). 3 A (DMSO-d₆): δ 8.25 (s, 2 H); 8.12 (d, J= 9.9 Hz, Formate 1 H); 7.95 (d, J = 8.0 Hz, 2 H); 7.56 (d, J = 8.0 Hz,2 H); 7.37 (d, J = 2.0 Hz, 1 H); 7.32-7.14 (m, 8 H); 7.08-7.02 (m, 2 H);6.98-6.86 (m, 3 H); 6.47 (d, J = 9.9 Hz, 1 H); 5.82 (d, J = 8.0 Hz, 1H); 5.17 (s, 2 H); 5.06 (dd, J = 7.9, 4.4 Hz, 1 H); 4.65-4.54 (m, 3 H);4.41 (d, J = 4.8 Hz, 2 H); 3.69 (s, 2 H); 3.11 (d, J = 13.0 Hz, 1 H);2.77-2.55 (m, 5 H); 1.91 (s, 1 H); 1.79 (s, 1 H); 1.63-1.31 (m, 4 H). 4A (DMSO-d₆): δ 8.32-8.20 (m, 2 H); Formate 8.11 (d, J = 9.9 Hz, 1 H);7.96 (d, J = 8.0 Hz, 2 H); 7.56 (d, J = 8.0 Hz, 2 H); 7.32-7.17 (m, 6H); 7.10-6.82 (m, 8 H); 6.47 (d, J = 9.9 Hz, 1 H); 5.81 (s, 1 H);5.18-5.06 (m, 3 H); 4.58 (m, 3 H); 4.30 (s, 2 H); 3.76 (s, 2 H); 3.71(s, 3 H); 3.14 (m, 1 H); 2.81-2.63 (m, 6 H); 1.93 (s, 1 H); 1.81 (s, 1H); 1.73-1.25 (m, 4 H). 5 C (DMSO-d₆): δ 8.27 (s, 2 H); 8.12 (d, J = 9.9Hz, Formate 1 H); 7.96 (d, J = 7.9 Hz, 2 H); 7.58-7.52 (m, 3 H);7.34-7.11 (m, 8 H); 7.09-7.00 (m, 2 H); 6.97-6.85 (m, 3 H); 6.47 (d, J =9.8 Hz, 1 H); 5.81 (s, 1 H); 5.16 (s, 2 H); 5.07 (dd, J = 8.0, 4.5 Hz, 1H); 4.61 (s, 3 H); 4.41 (s, 2 H); 3.70 (s, 2 H); 3.12 (d, J = 11.3 Hz, 1H); 2.81-2.51 (m, 5 H); 1.92 (s, 1 H); 1.80 (s, 1 H); 1.59 (s, 1 H);1.48 (s, 2 H); 1.35 (s, 2 H). 6 C (DMSO-d₆): δ 10.32 (s, 1 H); Formate8.33-8.16 (m, 2 H); 8.14 (d, J = 9.9 Hz, 1 H); 7.96 (d, J = 8.1 Hz, 2H); 7.56 (d, J = 8.0 Hz, 2 H); 7.30-7.16 (m, 7 H); 7.15-7.01 (m, 4 H);6.97-6.85 (m, 3 H); 6.47 (d, J = 9.9 Hz, 1 H); 5.81 (d, J = 9.1 Hz, 1H); 5.17 (s, 2 H); 5.05 (dd, J = 7.8, 4.5 Hz, 1 H); 4.69-4.55 (m, 3 H);4.44-4.39 (m, 2 H); 3.85-3.74 (m, 2 H); 3.24-3.07 (m, 1 H); 2.81-2.40(m, 7 H); 1.92 (s, 1 H); 1.80 (s, 1 H); 1.70-1.26 (m, 3 H). 7 C(DMSO-d₆): δ 10.32 (s, 1 H); 8.25 (s, 2 Formate H); 8.21-8.08 (m, 3 H);7.99 (d, J = 8.1 Hz, 2 H); 7.58-7.44 (m, 4 H); 7.40 (d, J = 7.9 Hz, 1H); 7.30-7.16 (m, 6 H); 7.08-6.82 (m, 6 H); 6.46 (d, J = 9.9 Hz, 1 H);5.81 (d, J = 9.1 Hz, 1 H); 5.16 (s, 2 H); 5.10 (dd, J = 7.9, 4.6 Hz, 1H); 4.78 (s, 2 H); 4.58 (s, 1 H); 4.51 (s, 2 H); 4.14 (t, J = 3.4 Hz, 2H); 3.19-3.08 (m, 1 H); 2.87-2.62 (m, 7 H); 1.91 (s, 1 H); 1.79 (s, 1H); 1.68-1.25 (m, 3 H). 8 C (DMSO-d₆): δ 10.31 (s, 1 H); 8.23 (s, 2Formate H); 8.13 (d, J = 9.9 Hz, 1 H); 7.96 (d, J = 8.1 Hz, 2 H); 7.56(d, J = 8.0 Hz, 2 H); 7.37 (d, J = 8.5 Hz, 1 H); 7.31-7.17 (m, 6 H);7.09-7.02 (m, 3 H); 6.96-6.86 (m, 4 H); 5.81 (d, J = 9.1 Hz, 1 H); 5.17(s, 2 H); 5.04 (dd, J = 7.7, 4.4 Hz, 1 H); 4.59 (s, 3 H); 4.36 (d, J =4.8 Hz, 2 H); 3.75 (s, 2 H); 3.10 (m, 1 H); 2.75-2.61 (m, 8 H); 1.90 (s,1 H); 1.78 (s, 1 H); 1.62-1.29 (m, 3 H). 9 C (DMSO-d₆): δ 10.20 (s, 1H); Formate 8.29-8.20 (m, 2 H); 8.11 (d, J = 9.9 Hz, 1 H); 7.96 (d, J =8.1 Hz, 2 H); 7.56 (d, J = 8.0 Hz, 2 H); 7.31-7.17 (m, 7 H); 7.09-7.01(m, 2 H); 6.97-6.80 (m, 6 H); 6.46 (d, J = 9.9 Hz, 1 H); 5.81 (d, J =9.1 Hz, 1 H); 5.17 (s, 2 H); 5.07 (dd, J = 7.9, 4.4 Hz, 1 H); 4.60 (m, 3H); 4.33-4.28 (m, 2 H); 3.73 (s, 2 H); 3.11 (m, 1 H); 2.77-2.58 (m, 7H); 1.90 (s, 1 H); 1.78 (s, 1 H); 1.66-1.25 (m, 3 H). 10 D (DMSO-d₆): δ10.34 (s, 1 H); 8.28 (d, J = 9.7 Hz, Diformate 1 H); 8.21 (s, 2 H); 8.12(d, J = 9.9 Hz, 1 H); 8.00 (d, J = 8.1 Hz, 2 H); 7.60 (d, J = 8.0 Hz, 2H); 7.32-7.19 (m, 6 H); 7.09-7.02 (m, 2 H); 7.00-6.87 (m, 5 H); 6.48 (d,J = 9.9 Hz, 1 H); 5.83 (d, J = 8.6 Hz, 1 H); 5.19 (s, 2 H); 5.15-5.09(m, 1 H); 4.68-4.53 (m, 3 H); 4.08 (s, 2 H); 3.72 (s, 2 H); 3.32-3.16(m, 1 H); 2.87-2.56 (m, 7 H); 2.21 (s, 6 H); 1.96 (s, 1 H); 1.84 (s, 1H); 1.73-1.31 (m, 3 H). 11 A (DMSO-d₆): δ 10.29 (br s, 1 H); Formate8.27-8.19 (m, 2 H); 8.13 (d, J = 9.93 Hz, 1 H); 7.90 (d, J = 8.06 Hz, 2H); 7.54 (d, J = 8.00 Hz, 2 H); 7.32-7.18 (m, 6 H); 7.09-7.02 (m, 2 H);6.99-6.85 (m, 5 H); 6.45 (d, J = 9.86 Hz, 1 H); 5.82 (d, J = 7.84 Hz, 1H); 5.16 (s, 2 H); 5.07 (dd, J = 7.64, 4.41 Hz, 1 H); 4.59 (s, 1 H);4.53 (s, 2 H); 4.30 (s, 2 H); 3.74 (s, 3 H); 3.69 (s, 2 H); 3.13 (s, 1H); 2.78-2.55 (m, 7 H); 1.92 (s, 1 H); 1.80 (s, 1 H); 1.67-1.29 (m, 3H). 12 A (DMSO-d₆): δ 10.31 (br s, 1 H); 8.24 (s, Diformate 3 H); 8.11(d, J = 9.93 Hz, 1 H); 7.97 (d, J = 8.04 Hz, 2 H); 7.57 (d, J = 8.01 Hz,2 H); 7.33-7.15 (m, 8 H); 7.04 (t, J = 5.55 Hz, 2 H); 6.96-6.85 (m, 3H); 6.60 (d, J = 2.32 Hz, 1 H); 6.57-6.47 (m, 2 H); 5.81 (s, 1 H); 5.18(s, 2 H); 5.08 (dd, J = 7.86, 4.61 Hz, 1 H); 4.60 (s, 3 H); 4.34 (s, 2H); 3.73 (d, J = 3.93 Hz, 5 H); 3.13 (d, J = 12.40 Hz, 1 H); 2.77-2.62(m, 6 H); 1.92 (s, 1 H); 1.80 (s, 1 H); 1.71-1.25 (m, 3 H). 13 A(DMSO-d₆): δ 10.29 (br s, 1 H); Diformate 8.30-8.20 (m, 3 H); 8.12 (d, J= 9.93 Hz, 1 H); 7.96 (d, J = 8.05 Hz, 2 H); 7.56 (d, J = 8.00 Hz, 2 H);7.41 (s, 1 H); 7.32-7.18 (m, 6 H); 7.05 (d, J = 8.40 Hz, 2 H); 6.96-6.85(m, 3 H); 6.82 (s, 1 H); 6.47 (d, J = 9.86 Hz, 1 H); 5.82 (d, J = 7.95Hz, 1 H); 5.17 (s, 2 H); 5.03 (dd, J = 7.60, 4.58 Hz, 1 H); 4.63 (d, J =5.03 Hz, 2 H); 4.58 (s, 1 H); 4.46 (d, J = 4.85 Hz, 2 H); 3.88-3.70 (m,3 H); 3.63 (s, 2 H); 3.11 (d, J = 13.87 Hz, 1 H); 2.78-2.54 (m, 7 H);1.90 (s, 1 H); 1.79 (s, 1 H); 1.46 (t, J = 49.22 Hz, 3 H). 14 B(CH₃OH-d₆): δ 8.55 (s, 1 H); 8.28 (d, J = 9.87 Hz, Formate 1 H); 8.00(d, J = 8.13 Hz, 2 H); 7.50 (d, J = 8.09 Hz, 2 H); 7.32-7.21 (m, 5 H);7.16 (d, J = 8.16 Hz, 1 H); 7.06 (s, 2 H); 6.98 (d, J = 8.15 Hz, 1 H);6.95-6.87 (m, 4 H); 6.59 (d, J = 9.84 Hz, 1 H); 5.88 (s, 1 H); 5.20-5.13(m, 4 H); 4.90 (m, 1 H); 4.70-4.65 (m, 2 H); 4.43-4.39 (m, 2 H);4.13-4.05 (q, J = 10.6 Hz, 2 H); 3.51-3.48 (m, 1 H); 3.19-3.13 (m, 2 H);3.08 (d, J = 14.26 Hz, 2 H); 2.92-2.88 (m, 2 H); 2.26 (s, 1 H); 2.2-2.07(m, 1 H); 2.0-1.68 (m, 3 H) 15 A (CH₃OH-d₄): δ 8.53 (s, 2 H); 8.28 (d, J= 9.88 Hz, Diformate 1 H); 7.99 (d, J = 8.13 Hz, 2 H); 7.49 (d, J = 8.04Hz, 2 H); 7.31-7.12 (m, 10 H); 7.01 (d, J = 8.15 Hz, 1 H); 6.96-6.88 (m,3 H); 6.64 (d, J = 9.83 Hz, 1 H); 5.88 (s, 1 H); 5.31 (dd, J = 8.86,4.22 Hz, 1 H); 5.14 (s, 2 H); 4.90 (m, 2 H); 4.71-4.66 (m, 2 H);4.49-4.45 (m, 2 H); 4.01 (s, 2 H); 3.61-3.49 (m, 1 H); 3.25-3.16 (m, 2H); 3.18-3.08 (m, 3 H); 3.04-2.98 (m, 1 H); 2.28 (s, 1 H); 2.21-2.1 (m,1 H); 2.02-1.7 (m, 3 H). 16 A (DMSO-d₆): δ 10.29 (br s, 1 H); Formate8.30-8.19 (m, 2 H); 8.12 (d, J = 9.93 Hz, 1 H); 7.92 (d, J = 8.05 Hz, 2H); 7.56 (d, J = 8.00 Hz, 2 H); 7.32-7.18 (m, 6 H); 7.11-7.02 (m, 2 H);6.97-6.86 (m, 3 H); 6.63 (s, 2 H); 6.45 (d, J = 9.86 Hz, 1 H); 5.82 (d,J = 8.41 Hz, 1 H); 5.17 (s, 2 H); 5.10 (dd, J = 7.85, 4.46 Hz, 1 H);4.59 (s, 1 H); 4.46 (d, J = 5.00 Hz, 2 H); 4.18 (t, J = 3.94 Hz, 2 H);3.71 (s, 2 H); 3.65 (s, 6 H); 3.19-3.08 (m, 1 H); 2.77-2.62 (m, 7 H);1.93 (s, 1 H); 1.81 (s, 1 H) 1.70-1.25 (m, 3 H). 17 C (DMSO-d₆): δ 10.49(s, 2 H); 9.84 (s, 1 Di-trifluoro- H); 9.01 (s, 1 H); 8.77 (s, 1 H);8.45 (d, acetate J = 9.11 Hz, 1 H); 8.13 (d, J = 9.94 Hz, 1 H); 7.98 (d,J = 8.08 Hz, 2 H); 7.57 (d, J = 9.33 Hz, 3 H); 7.32-7.19 (m, 6 H); 7.13(d, J = 8.19 Hz, 1 H); 7.03 (s, 1 H); 7.02-6.86 (m, 4 H); 6.57 (d, J =9.87 Hz, 1 H); 6.17 (s, 1 H); 5.83 (d, J = 9.06 Hz, 1 H); 5.38 (d, J =8.92 Hz, 1 H); 5.17 (s, 2 H); 4.88-4.83 (m, 1 H); 4.66 (s, 2 H); 4.53(s, 2 H); 4.21-4.07 (m, 1 H); 3.87 (s, 3 H); 3.71-3.59 (m, 1 H);3.33-2.92 (m, 7 H); 2.23 (s, 1 H); 2.06 (d, J = 13.09 Hz, 1 H);1.90-1.72 (m, 3 H). 18 C (DMSO-d₆): δ 8.28-8.19 (m, 3 H); Diformate 8.17(d, J = 9.9 Hz, 1 H); 8.05 (s, 1 H); 7.94 (d, J = 7.8 Hz, 1 H); 7.72 (d,J = 7.7 Hz, 1 H); 7.58-7.52 (m, 1 H); 7.38 (d, J = 7.8 Hz, 2 H);7.31-7.17 (m, 7 H); 7.10-7.02 (m, 2 H); 6.96-6.86 (m, 3 H); 6.51 (d, J =9.9 Hz, 1 H); 5.81 (d, J = 9.0 Hz, 1 H); 5.33 (s, 2 H); 5.16 (s, 2 H);5.07 (dd, J = 7.5, 4.8 Hz, 1 H); 4.57 (s, 1 H); 3.10 (s, 1 H); 2.86-2.65(m, 8 H); 2.50 (m, 4 H); 1.90 (s, 1 H); 1.79 (s, 1 H); 1.46 (t, J = 49.4Hz, 3 H). 19 C (DMSO-d₆): δ 8.29 (s, 1 H); 8.16 (s, 1 Formate H); 7.96(d, J = 8.00 Hz, 2 H); 7.57 (d, J = 7.98 Hz, 2 H); 7.46 (t, J = 7.83 Hz,1 H); 7.32-7.17 (m, 7 H); 7.17-6.99 (m, 4 H); 6.96-6.85 (m, 3 H); 6.50(d, J = 9.84 Hz, 1 H); 5.80 (s, 1 H); 5.37 (s, 2 H); 5.18 (s, 2 H); 5.03(dd, J = 7.70, 4.49 Hz, 1 H); 4.56 (s, 1 H); 3.16 (s, 3 H); 2.86-2.69(m, 7 H); 2.68 (s, 1 H); 2.33 (s, 1 H); 1.89 (s, 1 H); 1.78 (s, 1 H);1.57 (s, 1 H); 1.46 (s, 1 H); 1.32 (s, 1 H). 20 C (DMSO-d₆): δ 8.28 (s,1 H); 8.23 (d, J = 9.5 Hz, Formate 1 H); 8.17 (d, J = 9.9 Hz, 1 H); 8.00(d, J = 8.0 Hz, 2 H); 7.58 (d, J = 8.0 Hz, 2 H); 7.31-7.17 (m, 6 H);7.15 (d, J = 7.6 Hz, 1 H); 7.09-7.05 (m, 2 H); 7.03 (s, 1 H); 6.99-6.84(m, 4 H); 6.51 (d, J = 9.9 Hz, 1 H); 5.81 (d, J = 9.2 Hz, 1 H); 5.32 (s,2 H); 5.18 (s, 2 H); 5.10-5.03 (m, 1 H); 4.56 (s, 1 H); 3.79 (s, 3 H);3.09 (m, 1 H); 2.82-2.65 (m, 11 H); 1.90 (d, J = 6.3 Hz, 1 H); 1.78 (s,1 H); 1.58 (s, 1 H); 1.46 (s, 1 H); 1.33 (s, 1 H). 21 B (DMSO-d₆): δ8.28-8.19 (m, 3 H); Diformate 8.17 (d, J = 9.9 Hz, 1 H); 8.05 (s, 1 H);7.95 (d, J = 7.8 Hz, 1 H); 7.72 (d, J = 7.6 Hz, 1 H); 7.57-7.51 (m, 1H); 7.33-7.17 (m, 10 H); 7.10-7.01 (m, 2 H); 6.96-6.85 (m, 3 H); 6.50(d, J = 9.9 Hz, 1 H); 5.81 (d, J = 8.8 Hz, 1 H); 5.34 (s, 2 H); 5.16 (s,2 H); 5.11-5.05 (m, 1 H); 4.58 (s, 1 H); 3.11 (m, 1 H); 2.95-2.60 (m, 11H); 1.91 (s, 1 H); 1.79 (s, 1 H); 1.59 (s, 1 H); 1.48 (s, 1 H); 1.34 (s,1 H). 22 B (DMSO-d6): δ 8.26 (s, 2 H); 8.17 (d, J = 9.9 Hz, Formate 1H); 8.04 (d, J = 8.0 Hz, 2 H); 7.61 (d, J = 8.0 Hz, 2 H); 7.48 (s, 1 H);7.41-7.22 (m, 9 H); 7.13-7.07 (m, 2 H); 7.01-6.90 (m, 3 H); 6.51 (d, J =9.9 Hz, 1 H); 5.86 (d, J = 8.6 Hz, 1 H); 5.39 (s, 2 H); 5.23 (s, 2 H);5.12 (dd, J = 7.9, 4.3 Hz, 1 H); 4.63 (s, 1 H); 3.85 (s, 2 H); 3.17 (d,J = 14.5 Hz, 1 H); 2.83-2.67 (m, 7 H); 1.96 (m, 2 H); 1.66 (s, 1 H);1.53 (s, 1 H); 1.39 (s, 1 H). 23 C (DMSO-d6): δ 8.62 (d, J = 2.2 Hz, 1H); Formate 8.24 (s, 2 H); 8.16 (d, J = 9.9 Hz, 1 H); 7.99 (d, J = 8.0Hz, 2 H); 7.86 (dd, J = 8.0, 2.2 Hz, 1 H); 7.57 (d, J = 8.0 Hz, 2 H);7.44 (d, J = 8.0 Hz, 1 H); 7.31-7.17 (m, 6 H); 7.07 (d, J = 8.1 Hz, 1H); 7.03 (s, 1 H); 6.95-6.84 (m, 3 H); 6.49 (d, J = 9.9 Hz, 1 H); 5.81(d, J = 9.0 Hz, 1 H); 5.38 (s, 2 H); 5.18 (s, 2 H); 5.09 (dd, J = 7.8,4.5 Hz, 1 H); 4.57 (s, 1 H); 3.88 (s, 2 H); 3.12 (m, 1 H); 2.82-2.60 (m,7 H); 1.91 (s, 1 H); 1.79 (s, 1 H); 1.66-1.28 (m, 3 H). 24 C (DMSO-d₆@85 C): δ 8.22 (s, 2 H); Formate 8.17 (d, J = 9.93 Hz, 1 H); 7.97-7.91(m, 2 H); 7.54 (t, J = 7.70 Hz, 3 H); 7.31-7.19 (m, 6 H); 7.07 (d, J =8.17 Hz, 1 H); 7.01 (s, 1 H); 6.95-6.86 (m, 3 H); 6.51-6.45 (m, 2 H);6.23 (d, J = 3.12 Hz, 1 H); 5.82 (d, J = 8.64 Hz, 1 H); 5.28 (s, 2 H);5.17 (s, 2 H); 5.03 (dd, J = 7.69, 4.73 Hz, 1 H); 4.60-4.57 (m, 1 H);3.76 (s, 2 H); 3.07 (dd, J = 15.45, 8.55 Hz, 3 H); 2.82-2.76 (m, 1 H);2.72-2.63 (m, 3 H); 2.62 (d, J = 4.93 Hz, 1 H); 2.59 (d, J = 4.88 Hz, 1H); 1.89 (d, J = 3.93 Hz, 1 H); 1.58 (d, J = 8.96 Hz, 1 H); 1.49-1.47(m, 1 H). 25 C (DMSO-d₆): δ 8.30-8.18 (m, 2 H); Formate 8.14 (d, J = 9.9Hz, 1 H); 7.96 (d, J = 8.1 Hz, 2 H); 7.57 (d, J = 8.0 Hz, 2 H);7.52-7.45 (m, 1 H); 7.31-7.15 (m, 8 H); 7.10-6.99 (m, 2 H); 6.95-6.84(m, 3 H); 6.47 (d, J = 9.9 Hz, 1 H); 5.81 (d, J = 9.0 Hz, 1 H); 5.37 (s,2 H); 5.18 (s, 2 H); 5.06 (dd, J = 7.8, 4.4 Hz, 1 H); 4.58 (s, 1 H);3.78 (s, 2 H); 3.12 (m, 1 H); 2.76-2.57 (m, 7 H); 1.91 (s, 1 H); 1.79(s, 1 H); 1.65-1.27 (m, 3 H). 26 C (DMSO-d₆): δ 8.28-8.19 (m, 2 H);Formate 8.10 (d, J = 9.9 Hz, 1 H); 7.96 (d, J = 8.0 Hz, 2 H); 7.56 (d, J= 8.0 Hz, 2 H); 7.39 (s, 1 H); 7.33-7.17 (m, 7 H); 7.08-6.97 (m, 3 H);6.96-6.85 (m, 3 H); 6.46 (d, J = 9.9 Hz, 1 H); 5.81 (d, J = 9.0 Hz, 1H); 5.31 (s, 2 H); 5.17 (s, 2 H); 5.07 (dd, J = 7.8, 4.5 Hz, 1 H); 4.58(s, 1 H); 3.81 (s, 3 H); 3.75 (s, 2 H); 3.12 (m, 1 H); 2.79-2.63 (m, 7H); 1.91 (s, 1 H); 1.79 (s, 1 H); 1.59 (s, 1 H); 1.48 (s, 1 H); 1.34 (s,1 H). 27 C (DMSO-d6): δ 8.23 (s, 3 H); 8.15 (d, J = 9.9 Hz, Diformate 1H); 7.95 (d, J = 8.1 Hz, 2 H); 7.57 (d, J = 8.0 Hz, 3 H); 7.30-7.17 (m,7 H); 7.07 (d, J = 8.1 Hz, 1 H); 7.03 (s, 1 H); 6.96-6.86 (m, 3 H); 6.60(s, 1 H); 6.49 (d, J = 9.9 Hz, 1 H); 5.81 (d, J = 8.8 Hz, 1 H); 5.29 (s,2 H); 5.18 (s, 2 H); 5.06 (dd, J = 7.6, 4.6 Hz, 1 H); 4.58 (s, 1 H);3.61 (s, 2 H); 3.12 (m, 1 H); 2.78-2.60 (m, 6 H); 1.91 (s, 1 H); 1.79(s, 1 H); 1.59 (s, 1 H); 1.48 (s, 1 H); 1.35 (s, 1 H). 28 B(DMSO-d6/D2O): δ 8.14 (d, J = 9.9 Hz, Trifluoro- 1 H); 8.01 (d, J = 8.1Hz, 2 H); 7.62 (d, J = 8.1 Hz, acetate 2 H); 7.35-7.22 (m, 8 H); 7.17(d, J = 8.2 Hz, 1 H); 7.05-6.99 (m, 3 H); 6.97-6.93 (m, 1 H); 6.61 (d, J= 9.9 Hz, 1 H); 5.87-5.84 (m, 1 H); 5.58 (s, 2 H); 5.21 (s, 2 H);4.95-4.88 (m, 1 H); 4.44 (s, 2 H); 3.75-3.63 (m, 1 H); 3.30-3.07 (m, 9H); 2.27 (s, 1 H); 2.10-1.76 (m, 3 H) 29 B (DMSO-d6): δ 8.23 (s, 3 H);8.13 (d, J = 9.9 Hz, Diformate 1 H); 7.98 (d, J = 8.0 Hz, 2 H); 7.56 (d,J = 8.0 Hz, 2 H); 7.46 (s, 1 H); 7.32-7.18 (m, 6 H); 7.10-6.99 (m, 3 H);6.97-6.84 (m, 3 H); 6.47 (d, J = 9.9 Hz, 1 H); 5.81 (d, J = 8.8 Hz, 1H); 5.26 (s, 2 H); 5.18 (s, 2 H); 5.06 (dd, J = 7.8, 4.5 Hz, 1 H); 4.58(s, 1 H); 3.92 (d, J = 2.6 Hz, 2 H); 3.12 (d, J = 14.2 Hz, 1 H);2.77-2.65 (m, 6 H); 1.91 (s, 1 H); 1.80 (s, 1 H); 1.59 (s, 1 H); 1.48(s, 2 H); 1.35 (s, 1 H). 30 A (DMSO-d6): δ 8.27-8.19 (m, 3 H); Diformate8.11 (d, J = 9.9 Hz, 1 H); 8.05 (s, 1 H); 7.94 (d, J = 7.7 Hz, 1 H);7.72 (d, J = 7.7 Hz, 1 H); 7.57-7.51 (m, 1 H); 7.43 (s, 1 H); 7.35-7.16(m, 9 H); 7.08-7.02 (m, 2 H); 6.96-6.85 (m, 3 H); 6.46 (d, J = 9.9 Hz, 1H); 5.81 (d, J = 9.0 Hz, 1 H); 5.35 (s, 2 H); 5.16 (s, 2 H); 5.07 (dd, J= 8.0, 4.3 Hz, 1 H); 4.58 (s, 1 H); 3.79 (s, 2 H); 3.12 (m, 1 H);2.77-2.63 (m, 7 H); 1.91 (s, 1 H); 1.80 (s, 1 H); 1.59 (s, 1 H); 1.48(s, 1 H); 1.35 (s, 1 H). 31 C (DMSO-d₆): δ 10.53 (d, J = 7.72 Hz, 2Di-trifluoro- H); 9.59 (s, 1 H); 8.83 (s, 2 H); 8.49 (d, acetate J =9.18 Hz, 1 H); 8.13 (d, J = 9.95 Hz, 1 H); 8.07 (d, J = 8.14 Hz, 2 H);7.64 (d, J = 8.14 Hz, 2 H); 7.51 (d, J = 7.73 Hz, 1 H); 7.39-7.25 (m, 6H); 7.17 (t, J = 8.05 Hz, 2 H); 7.09-6.98 (m, 3 H); 6.96 (dd, J = 8.21,2.42 Hz, 1 H); 6.62 (dd, J = 9.87, 2.00 Hz, 1 H); 6.23 (d, J = 3.80 Hz,1 H); 5.88 (d, J = 9.09 Hz, 1 H); 5.46-5.35 (m, 2 H); 5.23 (s, 2 H);4.93-4.88 (m, 1 H); 4.30 (d, J = 13.50 Hz, 2 H); 3.92 (s, 3 H); 3.71 (t,J = 10.79 Hz, 1 H); 3.38-3.09 (m, 6 H); 3.11 (s, 3 H); 2.28 (s, 1 H);1.98-1.78 (m, 3 H). 31A C (DMSO-d₆): δ 10.54 (d, J = 9.45 Hz, 2 Di- H);9.61 (s, 1 H); 9.23 (s, 2 H); 8.49 (d, trifluoroacetate J = 9.16 Hz, 1H); 8.15 (d, J = 9.94 Hz, 1 H); 8.07 (d, J = 8.16 Hz, 2 H); 7.98 (s, 1H); 7.66 (d, J = 8.13 Hz, 2 H); 7.37-7.25 (m, 6 H); 7.18 (d, J = 8.17Hz, 1 H); 7.10-7.00 (m, 3 H); 6.96 (dd, J = 8.23, 2.40 Hz, 1 H);6.64-6.60 (m, 1 H); 6.23 (s, 1 H); 5.89 (d, J = 9.06 Hz, 1 H); 5.70 (s,2 H); 5.37 (d, J = 9.50 Hz, 1 H); 5.24 (s, 2 H); 4.93-4.88 (m, 1 H);4.58 (s, 2 H); 3.71 (t, J = 11.18 Hz, 1 H); 3.35-3.09 (m, 6 H); 2.28 (s,1 H); 1.88 (d, J = 40.12 Hz, 3 H). 31B C (DMSO-d₆): δ 10.51 (d, J = 11.5Hz, 2 Di- H); 9.51 (s, 3 H); 8.46 (d, J = 9.2 Hz, 1 trifluoroacetate H);8.14 (d, J = 9.9 Hz, 1 H); 8.00 (d, J = 8.1 Hz, 2 H); 7.60 (d, J = 8.1Hz, 2 H); 7.32-7.19 (m, 6 H); 7.14 (d, J = 8.2 Hz, 1 H); 7.00 (t, J =8.3 Hz, 3 H); 6.91 (dd, J = 8.3, 2.5 Hz, 1 H); 6.84 (s, 1 H); 6.59 (dd,J = 9.9, 1.9 Hz, 1 H); 6.21 (s, 1 H); 5.84 (d, J = 9.1 Hz, 1 H); 5.48(s, 2 H); 5.36 (d, J = 9.6 Hz, 1 H); 5.19 (s, 2 H); 4.88-4.83 (m, 1 H);4.53 (s, 2 H); 3.71-3.58 (m, 1 H); 3.28-3.05 (m, 4 H); 2.23 (s, 1 H);2.14-1.47 (m, 5 H). 31C C (DMSO-d₆): δ 8.23 (s, 2 H); 8.16 (d, J = 9.9Hz, Formate 1 H); 7.95 (d, J = 8.1 Hz, 2 H); 7.56 (d, J = 8.0 Hz, 2 H);7.31-7.17 (m, 7 H); 7.09-7.01 (m, 2 H); 6.96-6.85 (m, 3 H); 6.48 (d, J =9.9 Hz, 1 H); 6.24 (s, 1 H); 5.81 (d, J = 9.1 Hz, 1 H); 5.19 (d, J =14.3 Hz, 4 H); 5.04 (dd, J = 7.9, 4.4 Hz, 1 H); 4.58 (s, 1 H); 3.81-3.71(m, 5 H); 3.20-3.05 (m, 1 H); 2.78-2.60 (m, 5 H); 1.91 (s, 1 H); 1.79(s, 1 H); 1.59 (s, 1 H); 1.48 (s, 1 H); 1.34 (s, 1 H). 32 C (DMSO-d₆): δ10.29 (s, 1 H); Formate 8.28-8.20 (m, 2 H); 8.11 (d, J = 9.92 Hz, 1 H);7.96 (d, J = 8.06 Hz, 2 H); 7.56 (d, J = 7.98 Hz, 2 H); 7.32-7.15 (m, 10H); 7.07-7.02 (m, 2 H); 6.96-6.85 (m, 3 H); 6.46 (d, J = 9.87 Hz, 1 H);5.82 (d, J = 9.23 Hz, 1 H); 5.18 (s, 2 H); 5.06 (m, 1 H); 4.57 (m, 1 H);4.29-4.22 (t, J = 6.34 Hz, 2 H); 3.72 (s, 2 H); 3.10 (m, 1 H); 2.75-2.60(m, 7 H); 2.08-1.96 (m, 3 H); 1.90 (s, 1 H); 1.79 (s, 1 H); 1.62-1.26(m, 4 H). 33 A (DMSO-d₆): δ 8.30-8.18 (m, 2 H); Formate 8.11 (d, J = 9.9Hz, 1 H); 7.91 (d, J = 8.0 Hz, 2 H); 7.54 (d, J = 8.0 Hz, 2 H);7.32-7.15 (m, 8 H); 7.07-7.01 (m, 2 H); 6.97-6.85 (m, 3 H); 6.46 (d, J =9.8 Hz, 1 H); 5.82 (d, J = 9.2 Hz, 1 H); 5.16 (s, 2 H); 5.05 (dd, J =8.0, 4.3 Hz, 1 H); 4.56 (s, 1 H); 4.50-4.42 (m, 2 H); 3.71 (s, 2 H);3.10-2.98 (m, 3 H); 2.74-2.59 (m, 6 H); 1.99-1.32 (m, 8 H). 34 A(DMSO-d₆): δ 8.29-8.18 (m, 2 H); Formate 8.17 (d, J = 9.9 Hz, 1 H); 7.94(d, J = 8.1 Hz, 2 H); 7.84 (s, 1 H); 7.57-7.50 (m, 3 H); 7.31-7.17 (m, 6H); 7.08 (d, J = 8.1 Hz, 1 H); 7.02 (s, 1 H); 6.96-6.90 (m, 2 H); 6.88(dd, J = 8.2, 2.5 Hz, 1 H); 6.51 (d, J = 9.9 Hz, 1 H); 5.81 (d, J = 9.0Hz, 1 H); 5.21 (s, 2 H); 5.16 (s, 2 H); 5.10-5.04 (m, 1 H); 4.63-4.53(m, 1 H); 4.17-4.10 (m, 2 H); 3.15-3.09 (m, 2 H); 2.75-2.48 (m, 8 H);1.97-1.88 (m, 3 H); 1.85-1.72 (m, 1 H); 1.68-1.52 (m, 1 H); 1.55-1.40(m, 1 H); 1.42-1.27 (m, 1 H). 35 C ¹H NMR (400 MHz, DMSO): δ 10.50 (s,Di-trifluoro- 2 H); 9.66 (s, 1 H); 8.87 (s, 2 H); acetate 8.46 (d, J =9.2 Hz, 1 H); 8.08 (d, J = 9.9 Hz, 1 H); 7.95 (s, 1 H); 7.87 (d, J = 8.1Hz, 2 H); 7.61 (s, 1 H); 7.51 (d, J = 8.1 Hz, 2 H); 7.33-7.20 (m, 6 H);7.10 (d, J = 8.2 Hz, 1 H); 7.04-6.93 (m, 3 H); 6.90 (dd, J = 8.2, 2.4Hz, 1 H); 6.56 (d, J = 9.9 Hz, 1 H); 6.17 (s, 1 H); 5.84 (d, J = 9.1 Hz,1 H); 5.30 (d, J = 9.4 Hz, 1 H); 5.15 (s, 2 H); 4.89-4.84 (m, 1 H); 4.57(dd, J = 19.0, 5.3 Hz, 4 H); 4.10 (s, 3 H); 3.67 (t, J = 12.4 Hz, 2 H);3.31-2.98 (m, 5 H); 2.24 (s, 1 H); 2.12-1.72 (m, 3 H). 36 A (DMSO-d₆): δ8.48-8.07 (m, 3 H); Diformate 8.18 (d, J = 9.93 Hz, 1 H); 7.33-7.19 (m,6 H); 7.13-7.04 (m, 2 H); 7.00-6.90 (m, 3 H); 6.88 (s, 1 H); 6.51 (d, J= 9.86 Hz, 1 H); 5.83 (d, J = 8.56 Hz, 1 H); 5.32-5.03 (m, 3 H); 4.60(s, 2 H); 4.26-4.19 (m, 2 H); 4.10-3.66 (m, 3 H); 3.20-3.08 (m, 1 H);2.93-2.54 (m, 9 H); 2.06-1.28 (m, 8 H). 37 C (DMSO-d₆): δ 8.30-8.20 (m,2 H); Formate 8.18 (d, J = 9.9 Hz, 1 H); 7.93 (s, 1 H); 7.82 (d, J = 1.5Hz, 1 H); 7.34-7.26 (m, 4 H); 7.28-7.18 (m, 2 H); 7.09 (d, J = 8.2 Hz, 1H); 7.02 (s, 1 H); 6.94 (d, J = 8.0 Hz, 2 H); 6.88 (dd, J = 8.2, 2.5 Hz,1 H); 6.51 (d, J = 9.9 Hz, 1 H); 5.82 (d, J = 8.2 Hz, 1 H); 5.16-5.11(m, 1 H); 5.07 (s, 2 H); 4.58 (s, 1 H); 4.28-4.21 (m, 2 H); 3.11 (d, J =11.1 Hz, 1 H); 2.85-2.58 (m, 7 H); 1.96-1.33 (m, 11 H) 38 C (DMSO-d₆): δ9.06 (d, J = 2.1 Hz, 1 H); Diformate 8.89 (d, J = 2.2 Hz, 1 H); 8.35 (s,1 H); 8.36-8.16 (m, 3 H); 8.21-8.12 (m, 1 H); 7.32-7.18 (m, 7 H);7.11-7.04 (m, 2 H); 6.99-6.89 (m, 3 H); 6.51 (dd, J = 9.8, 5.1 Hz, 1 H);5.83 (d, J = 8.8 Hz, 1 H); 5.23 (s, 2 H); 5.14-5.07 (m, 1 H); 4.57 (s, 1H); 4.36-4.29 (m, 2 H); 3.10 (m, 1 H); 2.82-2.70 (m, 6 H); 1.90 (s, 1H); 1.81-1.71 (m, 4 H); 1.65-1.55 (m, 4 H); 1.48 (s, 1 H); 1.34 (s, 1H). 39 C (DMSO-d₆): δ 10.30 (br s, 1 H); Diformate 8.48-8.07 (m, 3 H);8.21-8.10 (m, 2 H); 7.34-7.19 (m, 6 H); 7.15-7.04 (m, 2 H); 7.00-6.91(m, 2 H); 6.75 (s, 1 H); 6.53 (d, J = 9.86 Hz, 1 H); 5.84 (d, J = 8.57Hz, 1 H); 5.31-5.10 (m, 3 H); 4.61 (s, 1 H); 3.88 (s, 3 H); 3.31-2.97(m, 3 H); 2.95-2.56 (m, 7 H); 1.94 (s, 1 H); 1.82 (s, 1 H); 1.73-1.16(m, 9 H). 39A C (DMSO-d₆, 105° C.): δ 8.25-8.16 (m, 3 Diformate H); 7.59(s, 1 H); 7.34-7.19 (m, 6 H); 7.13-7.01 (m, 2 H); 6.98-6.91 (m, 3 H);6.57 (s, 1 H); 6.48 (d, J = 9.9 Hz, 1 H); 5.84 (d, J = 7.5 Hz, 1 H);5.21-5.12 (m, 2 H); 5.05 (dd, J = 7.4, 5.1 Hz, 1 H); 4.66-4.60 (m, 1 H);3.93-3.81 (m, 3 H); 3.55 (d, J = 8.2 Hz, 4 H); 3.10 (dd, J = 14.4, 8.3Hz, 1 H); 2.86-2.59 (m, 9 H); 1.94-1.90 (m, 1 H); 1.79-1.68 (m, 3 H);1.67-1.56 (m, 1 H); 1.54-1.44 (m, 1 H); 1.37-1.26 (m, 1 H); 1.19-1.08(m, 3 H). 39B C (DMSO-d₆): δ 8.66-8.60 (m, 1 H); Diformate 8.31-8.23 (m,3 H); 8.11 (d, J = 9.9 Hz, 1 H); 7.33-7.18 (m, 10 H); 7.06 (d, J = 8.7Hz, 2 H); 6.99-6.90 (m, 3 H); 6.79 (s, 1 H); 6.49 (dd, J = 9.9, 4.3 Hz,1 H); 5.83 (d, J = 9.3 Hz, 1 H); 5.20 (s, 2 H); 5.10 (dd, J = 7.8, 4.7Hz, 1 H); 4.62 (s, 2 H); 4.39 (d, J = 6.3 Hz, 2 H); 3.89 (s, 3 H);3.93-3.61 (m, 2 H); 3.16 (d, J = 11.7 Hz, 1 H); 2.87-2.53 (m, 6 H); 1.95(s, 1 H); 1.83 (s, 1 H); 1.62 (s, 1 H); 1.52 (s, 1 H); 1.39 (s, 1 H).39C C (DMSO-d₆): δ 10.54 (s, 1 H); 10.49 (s, 1 Di- H); 9.84 (s, 1 H);8.71 (t, J = 6.6 Hz, 1 trifluoroacetate H); 8.47 (d, J = 9.2 Hz, 1 H);8.08 (d, J = 9.9 Hz, 1 H); 7.38-6.87 (m, 16 H); 6.79 (s, 1 H); 6.56 (d,J = 9.9 Hz, 1 H); 6.20 (s, 1 H); 5.84 (d, J = 9.1 Hz, 1 H); 5.34 (s, 1H); 5.20 (s, 2 H); 4.89-4.84 (m, 1 H); 4.43 (d, J = 6.3 Hz, 2 H);4.28-4.11 (m, 2 H); 3.90 (s, 3 H); 3.81 (s, 3 H); 3.66 (t, J = 18.0 Hz,1 H); 3.38-2.92 (m, 7 H); 2.23 (s, 1 H); 2.06 (d, J = 15.5 Hz, 1 H);1.96-1.68 (m, 3 H). 39D C (DMSO-d₆): δ 8.72 (t, J = 6.3 Hz, 1 H);Diformate 8.30 (d, J = 9.6 Hz, 1 H); 8.25 (s, 2 H); 8.20-8.09 (m, 1 H);7.40-7.16 (m, 7 H); 7.11-6.89 (m, 7 H); 6.80 (s, 1 H); 6.55-6.45 (m, 1H); 5.83 (d, J = 9.3 Hz, 1 H); 5.20 (s, 2 H); 5.06 (dd, J = 8.1, 4.5 Hz,1 H); 4.65 (s, 2 H); 4.39 (d, J = 6.2 Hz, 2 H); 3.90 (s, 3 H); 3.77 (s,2 H); 3.23 (t, J = 10.2 Hz, 1 H); 2.87-2.56 (m, 6 H); 1.99 (s, 1 H);1.86 (d, J = 11.1 Hz, 1 H); 1.65 (s, 1 H); 1.55 (s, 1 H); 1.43 (s, 1 H).40 C (DMSO-d₆): δ 10.38 (br s, 1 H); Diformate 8.46-8.39 (m, 1 H);8.33-8.21 (m, 3 H); 8.18 (d, J = 9.93 Hz, 1 H); 7.34-7.19 (m, 6 H); 7.11(d, J = 8.15 Hz, 1 H); 7.05 (t, J = 3.66 Hz, 2 H); 6.99-6.89 (m, 3 H);6.69 (d, J = 3.44 Hz, 1 H); 6.54 (d, J = 9.86 Hz, 1 H); 5.84 (d, J =8.95 Hz, 1 H); 5.20 (dd, J = 8.44, 4.14 Hz, 1 H); 5.08 (s, 2 H); 4.60(s, 1 H); 3.28-3.01 (m, 3 H); 2.88 (d, J = 8.88 Hz, 2 H); 2.79 (s, 6 H);1.93 (s, 1 H); 1.88-1.73 (m, 1 H); 1.74-1.15 (m, 7 H). 40A C (DMSO-d₆,105° C.): δ 8.24-8.14 (m, 3 Diformate H); 7.57 (d, J = 8.8 Hz, 1 H);7.33-7.27 (m, 4 H); 7.26-7.19 (m, 2 H); 7.08 (d, J = 8.1 Hz, 1 H); 7.01(d, J = 2.3 Hz, 1 H); 6.97-6.89 (m, 3 H); 6.86 (d, J = 3.4 Hz, 1 H);6.57 (d, J = 3.4 Hz, 1 H); 6.48 (d, J = 9.9 Hz, 1 H); 5.83 (d, J = 8.2Hz, 1 H); 5.15-5.04 (m, 2 H); 5.03 (dd, J = 7.5, 4.9 Hz, 1 H); 3.51-3.43(m, 4 H); 3.09 (dd, J = 14.4, 8.3 Hz, 1 H); 2.85-2.51 (m, 10 H);1.93-1.89 (m, 1 H); 1.78-1.65 (m, 3 H); 1.66-1.57 (m, 1 H); 1.52-1.44(m, 1 H); 1.34-1.26 (m, 1 H); 1.17-1.09 (m, 3 H). 41 B (DMSO-d₆): δ10.31 (br s, 1 H); 8.61 (s, Formate 1 H); 8.37 (t, J = 6.01 Hz, 1 H);8.37-8.17 (m, 2 H); 8.17 (d, J = 9.92 Hz, 1 H); 7.33-7.19 (m, 6 H); 7.10(d, J = 8.15 Hz, 1 H); 7.05-6.86 (m, 4 H); 6.53 (d, J = 9.86 Hz, 1 H);5.83 (d, J = 8.65 Hz, 1 H); 5.25-5.14 (m, 3 H); 4.59 (s, 1 H); 3.23 (d,J = 6.27 Hz, 2 H); 3.21-3.06 (m, 1 H); 2.86-2.52 (m, 8 H); 1.92 (s, 1H); 1.80 (s, 1 H); 1.71-1.16 (m, 8 H). 41A C (DMSO-d₆): 8.49-8.42 (m, 1H), 8.28 (d, Diformate J = 6.31 Hz, 3 H), 8.18 (d, J = 9.94 Hz, 1 H),7.33-7.19 (m, 7 H), 7.15-7.07 (m, 2 H), 7.02 (d, J = 7.70 Hz, 1 H), 6.96(d, J = 8.14 Hz, 2 H), 6.54 (d, J = 9.87 Hz, 1 H), 5.85 (s, 1 H), 5.43(s, 2 H), 5.19 (dd, J = 8.25, 4.35 Hz, 1 H), 4.60 (s, 1 H), 3.29-3.04(m, 3 H), 2.93-2.57 (m, 7 H), 1.93 (s, 1 H), 1.81 (s, 2 H), 1.68-1.20(m, 8 H). 41B C (DMSO-d₆): δ 10.35 (s, 1 H); Diformate 8.63-8.56 (m, 1H); 8.35 (d, J = 9.20 Hz, 1 H); 8.28-8.22 (m, 3 H); 7.95 (s, 1 H); 7.82(d, J = 7.77 Hz, 1 H); 7.59 (d, J = 7.62 Hz, 1 H); 7.47 (t, J = 7.66 Hz,1 H); 7.34-7.20 (m, 6 H); 7.18-7.09 (m, 1 H); 7.10-6.84 (m, 4 H); 6.55(d, J = 9.85 Hz, 1 H); 5.84 (d, J = 9.15 Hz, 1 H); 5.40 (d, J = 9.38 Hz,1 H); 5.12 (s, 2 H); 4.74-4.68 (m, 1 H); 3.38-3.18 (m, 3 H); 3.06-2.66(m, 8 H); 2.05 (s, 1 H); 1.91 (s, 1 H); 1.75-1.45 (m, 7 H). 41C C(DMSO-d₆): δ 8.43-8.36 (m, 1 H); Diformate 8.30 (s, 2 H); 8.24 (d, J =9.5 Hz, 1 H); 8.17 (d, J = 9.9 Hz, 1 H); 7.89 (s, 1 H); 7.35-7.27 (m, 4H); 7.27-7.18 (m, 2 H); 7.16-7.06 (m, 2 H); 7.01 (s, 1 H); 6.95 (d, J =8.0 Hz, 2 H); 6.88 (dd, J = 8.3, 2.5 Hz, 1 H); 6.52 (d, J = 9.9 Hz, 1H); 5.83 (d, J = 9.2 Hz, 1 H); 5.16-5.11 (m, 1 H); 4.95 (s, 2 H); 4.58(s, 1 H); 3.11 (d, J = 14.4 Hz, 2 H); 2.85-2.70 (m, 7 H); 1.91 (s, 1 H);1.80 (s, 1 H); 1.66-1.20 (m, 9 H). 42 C (DMSO-d₆) □ 9.87-10.55 (bs, 1H), Hydrochloride 8.52 (d, J = 9.26 Hz, 1 H), 8.33 (s, 2 H), 8.11-8.20(m, 2 H), 8.05 (d, J = 3.53 Hz, 1 H), 7.17-7.46 (m, 7 H), 6.87-7.10 (m,5 H), 6.74 (d, J = 3.53 Hz, 1 H), 6.48 (d, J = 9.70 Hz, 1 H), 5.84 (d, J= 9.26 Hz, 1 H), 4.93-5.23 (m, 6 H), 4.23 (t, J = 6.39 Hz, 2 H),3.98-4.12 (m, 2 H), 3.52-3.75 (m, 4 H), 2.57-2.80 (m, 4 H), 2.32 (m, 1H), 1.86-2.23 (m, 4 H), 1.60-1.77 (m, 2 H), 1.44-1.57 (m, 2 H) 43 C(DMSO-d₆): δ 9.06-9.00 (m, 1 H); Diformate 8.31-8.23 (m, 3 H); 8.12 (d,J = 9.9 Hz, 1 H); 7.90 (d, J = 8.1 Hz, 2 H); 7.52 (d, J = 8.0 Hz, 2 H);7.32-7.17 (m, 10 H); 7.05 (t, J = 4.2 Hz, 2 H); 6.96-6.85 (m, 3 H);6.53-6.45 (m, 1 H); 5.82 (d, J = 9.2 Hz, 1 H); 5.18-5.06 (m, 3 H); 4.62(s, 2 H); 4.47 (d, J = 5.9 Hz, 2 H); 3.92-3.68 (m, 2 H); 2.88-2.51 (m, 7H); 1.95 (s, 1 H); 1.83 (s, 1 H); 1.62 (s, 1 H); 1.52 (s, 1 H); 1.39 (s,1 H). 44 C (DMSO-d₆): δ 9.05-8.99 (m, 1 H); Formate 8.29-8.21 (m, 2 H);8.12 (d, J = 9.9 Hz, 1 H); 7.90 (d, J = 8.1 Hz, 2 H); 7.52 (d, J = 8.0Hz, 2 H); 7.33-7.19 (m, 7 H); 7.05 (d, J = 7.8 Hz, 2 H); 6.97-6.81 (m, 5H); 6.49 (d, J = 9.9 Hz, 1 H); 5.82 (d, J = 9.1 Hz, 1 H); 5.14 (s, 2 H);5.07 (dd, J = 7.8, 4.6 Hz, 1 H); 4.60 (s, 1 H); 4.47 (d, J = 5.8 Hz, 2H); 3.78-3.62 (m, 3 H); 3.23-3.06 (m, 1 H); 2.84-2.55 (m, 7 H); 2.08 (s,2 H); 1.93 (t, J = 4.4 Hz, 1 H); 1.82 (s, 1 H); 1.61 (s, 1 H); 1.50 (s,1 H); 1.37 (s, 1 H). 45 C (DMSO-d₆, 120° C.): δ 8.21 (d, J = 9.9 Hz,Diformate 1 H); 8.16 (s, 2 H); 7.47-7.38 (m, 1 H); 7.32-7.27 (m, 4 H);7.26-7.20 (m, 2 H); 7.08 (d, J = 8.1 Hz, 1 H); 7.02-7.00 (m, 1 H);6.98-6.85 (m, 3 H); 6.48 (d, J = 9.9 Hz, 1 H); 6.41 (s, 1 H); 5.86-5.80(m, 1 H); 5.07-4.96 (m, 3 H); 4.65-4.59 (m, 1 H); 3.84-3.77 (m, 3 H);3.48-3.40 (m, 2 H); 3.09 (dd, J = 14.5, 8.3 Hz, 1 H); 2.96 (s, 3 H);2.81-2.47 (m, 9 H); 1.93-1.88 (m, 1 H); 1.80-1.56 (m, 4 H); 1.53-1.44(m, 1 H); 1.37-1.27 (m, 1 H). 46 C (DMSO-d₆, 120° C.): δ 8.21 (d, J =10.0 Hz, Diformate 1 H); 8.16 (s, 2 H); 7.47-7.40 (m, 1 H); 7.32-7.27(m, 4 H); 7.25-7.19 (m, 2 H); 7.08 (d, J = 8.1 Hz, 1 H); 7.01 (s, 1 H);6.97-6.86 (m, 3 H); 6.48 (d, J = 9.9 Hz, 1 H); 6.37 (s, 1 H); 5.85-5.80(m, 1 H); 5.06-4.98 (m, 3 H); 4.64-4.59 (m, 1 H); 3.82-3.75 (m, 3 H);3.46-3.34 (m, 4 H); 3.09 (dd, J = 14.4, 8.3 Hz, 1 H); 2.80-2.47 (m, 9H); 1.93-1.89 (m, 1 H); 1.79-1.56 (m, 4 H); 1.53-1.45 (m, 1 H);1.34-1.27 (m, 1 H); 1.10 (t, J = 7.1 Hz, 3 H). 47 C (DMSO-d₆, 105° C.):δ 8.24-8.15 (m, 3 Diformate H); 7.57 (s, 1 H); 7.46 (d, J = 7.9 Hz, 2H); 7.37-7.28 (m, 6 H); 7.27-7.21 (m, 2 H); 7.09 (d, J = 8.1 Hz, 1 H);7.03 (s, 1 H); 6.98-6.86 (m, 3 H); 6.49 (d, J = 9.9 Hz, 1 H); 5.83 (d, J= 7.0 Hz, 1 H); 5.21-5.04 (m, 2 H); 5.07-5.00 (m, 1 H); 4.64-4.59 (m, 2H); 3.13-3.05 (m, 1 H); 2.92 (s, 3 H); 2.83-2.46 (m, 10 H); 1.91 (s, 1H); 1.76 (s, 1 H); 1.69-1.29 (m, 7 H). 48 C (DMSO-d₆, 105° C.): δ8.24-8.16 (m, 3 Diformate H); 7.58 (m, 1 H); 7.46 (d, J = 7.9 Hz, 2 H);7.34-7.28 (m, 6 H); 7.27-7.21 (m, 2 H); 7.10-7.02 (m, 2 H); 6.97-6.86(m, 3 H); 6.48 (d, J = 9.9 Hz, 1 H); 5.83 (d, J = 7.0 Hz, 1 H); 5.11 (s,2 H); 5.03 (dd, J = 7.4, 5.0 Hz, 1 H); 4.65-4.59 (m, 1 H); 3.39-3.25 (m,4 H); 3.15-3.04 (m, 1 H); 2.82-2.51 (m, 11 H); 1.93-1.89 (m, 1 H); 1.76(s, 1 H); 1.64-1.53 (m, 3 H); 1.42-1.30 (m, 2 H); 1.10 (t, J = 7.0 Hz, 3H). 49 C (DMSO-d₆, 105° C.): δ 8.23-8.13 (m, 3 Diformate H); 7.57 (m, 1H); 7.48-7.37 (m, 2 H); 7.33-7.27 (m, 6 H); 7.26-7.19 (m, 2 H);7.10-7.02 (m, 2 H); 6.96-6.85 (m, 3 H); 6.48 (d, J = 9.9 Hz, 1 H); 5.83(d, J = 7.9 Hz, 1 H); 5.12 (s, 2 H); 5.01 (m, 1 H); 4.64-4.59 (m, 1 H);3.43-3.31 (m, 2 H); 3.09 (m, 1 H); 2.89 (s, 3 H); 2.83-2.54 (m, 9 H);1.91 (s, 1 H); 1.77-1.56 (m, 5 H); 1.31 (d, J = 11.1 Hz, 1 H). 50 C(DMSO-d₆, 105° C.): δ 8.23-8.15 (m, 3 Diformate H); 7.57 (s, 1 H);7.49-7.34 (m, 3 H); 7.33-7.19 (m, 7 H); 7.07 (d, J = 8.1 Hz, 1 H);7.04-7.02 (m, 1 H); 6.97-6.85 (m, 3 H); 6.48 (d, J = 9.9 Hz, 1 H); 5.83(d, J = 8.0 Hz, 1 H); 5.29-4.95 (m, 2 H); 5.02 (dd, J = 7.7, 5.1 Hz, 1H); 4.65-4.59 (m, 1 H); 3.42-3.22 (m, 4 H); 3.09 (m, 1 H); 2.83-2.54 (m,9 H); 1.93-1.89 (m, 1 H); 1.75-1.54 (m, 4 H); 1.54-1.44 (m, 1 H);1.37-1.26 (m, 1 H); 1.12-1.02 (m, 3 H). 51 C (DMSO-d₆, 110° C.): δ8.21-8.15 (m, 2 Di- H); 7.86-7.78 (m, 3 H); 7.54-7.23 (m, 13trifluoroacetate H); 7.15 (d, J = 8.2 Hz, 1 H); 7.05-6.95 (m, 3 H); 6.93(dd, J = 8.3, 2.7 Hz, 1 H); 6.55 (d, J = 9.9 Hz, 1 H); 5.87-5.82 (m, 1H); 5.36-5.31 (m, 1 H); 5.15-5.08 (m, 2 H); 4.95-4.90 (m, 1 H); 3.66(ddd, J = 13.9, 8.5, 2.6 Hz, 1 H); 3.57-3.46 (m, 7 H); 3.59-2.72 (m, 9H); 2.25 (d, J = 4.6 Hz, 1 H); 2.10-1.72 (m, 7 H). 52 C (DMSO-d₆, 110°C.): δ 8.17 (d, J = 9.9 Hz, Di- 1 H); 7.86-7.77 (m, 2 H);trifluoroacetate 7.36-7.21 (m, 9 H); 7.15 (d, J = 8.2 Hz, 1 H);7.03-6.98 (m, 2 H); 6.95 (d, J = 7.8 Hz, 1 H); 6.90 (dd, J = 8.2, 2.5Hz, 1 H); 6.56 (d, J = 9.9 Hz, 1 H); 5.84 (d, J = 8.7 Hz, 1 H);5.35-5.30 (m, 1 H); 5.04 (s, 2 H); 4.95-4.90 (m, 1 H); 3.65 (ddd, J =13.8, 8.5, 2.5 Hz, 1 H); 3.47 (s, 2 H); 3.28-2.97 (m, 12 H); 2.26-2.23(m, 1 H); 2.07-1.73 (m, 6 H). 53 C (DMSO-d₆): δ 8.32-8.23 (m, 3 H);Diformate 8.11 (d, J = 9.9 Hz, 1 H); 7.63-7.33 (m, 4 H); 7.35-7.21 (m, 8H); 7.09-7.04 (m, 3 H); 6.96-6.88 (m, 3 H); 6.45 (d, J = 9.9 Hz, 1 H);5.84 (d, J = 9.1 Hz, 1 H); 5.17-5.08 (m, 3 H); 4.66-4.59 (m, 1 H); 3.83(s, 2 H); 3.76 (s, 3 H); 3.23-3.12 (m, 1 H); 2.85-2.51 (m, 7 H); 1.93(s, 1 H); 1.83 (s, 1 H); 1.62 (s, 1 H); 1.52 (s, 1 H); 1.39 (s, 1 H). 54C (DMSO-d₆): δ 8.30-8.19 (m, 3 H); Diformate 8.14 (d, J = 9.9 Hz, 1 H);7.70 (d, J = 8.0 Hz, 2 H); 7.51 (d, J = 7.9 Hz, 2 H); 7.39-7.17 (m, 10H); 7.07 (d, J = 8.4 Hz, 2 H); 6.97-6.87 (m, 3 H); 6.49 (d, J = 9.9 Hz,1 H); 5.83 (d, J = 9.0 Hz, 1 H); 5.14-5.06 (m, 3 H); 4.60 (s, 1 H); 3.86(s, 3 H); 3.80 (s, 2 H); 3.14 (t, J = 8.6 Hz, 1 H); 2.81-2.56 (m, 6 H);1.93 (s, 1 H); 1.82 (s, 1 H); 1.61 (s, 1 H); 1.50 (s, 1 H); 1.37 (s, 1H). 55 C (DMSO-d₆): δ 10.50 (s, 2 H); 9.61 (s, 1 Di- H); 8.90 (s, 3 H);8.46 (d, J = 9.2 Hz, 1 trifluoroacetate H); 8.08 (d, J = 9.9 Hz, 1 H);7.83 (d, J = 2.4 Hz, 1 H); 7.76 (dd, J = 8.6, 2.3 Hz, 1 H); 7.67 (d, J =8.1 Hz, 2 H); 7.52 (d, J = 8.0 Hz, 2 H); 7.34-7.17 (m, 6 H); 7.15 (d, J= 8.2 Hz, 1 H); 7.04 (s, 1 H); 6.98 (d, J = 8.1 Hz, 2 H); 6.92 (dd, J =8.2, 2.4 Hz, 1 H); 6.53 (d, J = 9.9 Hz, 1 H); 6.22 (s, 1 H); 5.84 (d, J= 9.1 Hz, 1 H); 5.10 (s, 2 H); 4.89-4.84 (m, 1 H); 4.32 (s, 2 H); 3.89(s, 3 H); 3.30-3.05 (m, 8 H); 2.24 (s, 1 H); 2.16-1.97 (m, 1 H);1.97-1.57 (m, 4 H). 56 C (DMSO-d₆): δ 8.31-8.20 (m, 3 H); Diformate 8.11(d, J = 9.9 Hz, 1 H); 7.41-7.27 (m, 8 H); 7.26-7.20 (m, 2 H); 7.12-7.00(m, 2 H); 6.94-6.83 (m, 3 H); 6.48 (d, J = 9.9 Hz, 1 H); 5.82 (d, J =9.3 Hz, 1 H); 5.10 (dd, J = 8.0, 4.5 Hz, 1 H); 5.04 (s, 2 H); 4.63-4.62(m, 1 H); 3.81 (s, 2 H); 3.27-3.08 (m, 1 H); 2.82 (br s, 2 H); 2.81-2.56(m, 5 H); 1.96 (br s, 1 H); 1.90-1.84 (m, 1 H); 1.70-1.60 (m, 1 H);1.63-1.46 (m, 1 H); 1.44-1.38 (m, 1 H). 57 C (DMSO-d₆): δ 8.29-8.18 (m,2 H); Diformate 8.15 (d, J = 9.9 Hz, 1 H); 7.35-7.27 (m, 4 H); 7.26-7.18(m, 2 H); 7.11-6.98 (m, 2 H); 6.95-6.85 (m, 3 H); 6.51-6.43 (m, 2 H);6.21 (d, J = 3.1 Hz, 1 H); 5.82 (d, J = 9.2 Hz, 1 H); 5.04 (dd, J = 8.0,4.5 Hz, 1 H); 4.97 (s, 2 H); 4.61 (s, 1 H); 3.73 (s, 2 H); 3.23-3.11 (m,1 H); 2.74-2.64 (m, 7 H); 1.94 (d, J = 5.2 Hz, 1 H); 1.82 (s, 1 H); 1.62(s, 1 H); 1.52 (s, 2 H); 1.39 (s, 1 H). 58 C (DMSO-d₆/D2O): δ 8.17 (d, J= 10.0 Hz, Di- 1 H); 7.40-7.20 (m, 10 H); 7.17 (d, J = 8.2 Hz,trifluoroacetate 1 H); 7.04-6.92 (m, 3 H); 6.93-6.87 (m, 1 H); 6.60 (d,J = 9.9 Hz, 1 H); 5.84-5.78 (m, 1 H); 5.31 (dd, J = 9.7, 3.4 Hz, 1 H);5.02 (s, 2 H); 4.87-4.82 (m, 1 H); 3.63-3.59 (m, 1 H); 3.28-3.07 (m, 8H); 3.03-2.90 (m, 2 H); 2.22 (s, 1 H); 2.03 (s, 1 H); 2.01-1.72 (m, 4H). 59 C (DMSO-d₆): δ 10.50 (d, J = 17.4 Hz, 2 Di- H); 9.53 (s, 1 H);9.06 (s, 2 H); 8.45 (d, trifluoroacetate J = 9.2 Hz, 1 H); 8.07 (d, J =9.9 Hz, 1 H); 7.60 (s, 1 H); 7.53-7.44 (m, 3 H); 7.32 (d, J = 4.5 Hz, 4H); 7.28-7.21 (m, 2 H); 7.12 (d, J = 8.2 Hz, 1 H); 7.02-6.94 (m, 4 H);6.90 (d, J = 8.3 Hz, 1 H); 6.57 (dd, J = 9.8, 1.9 Hz, 1 H); 6.17 (s, 1H); 5.84 (d, J = 9.1 Hz, 1 H); 5.33 (d, J = 9.4 Hz, 1 H); 5.07 (s, 2 H);4.89-4.84 (m, 1 H); 4.25 (s, 2 H); 3.72-3.60 (m, 1 H); 3.28-2.94 (m, 6H); 2.23 (s, 1 H); 2.04 (s, 1 H); 1.92-1.73 (m, 3 H). 60 C (DMSO-d₆): δ10.52 (s, 1 H); 10.47 (s, 1 Di- H); 9.53 (s, 1 H); 9.19 (s, 2 H); 8.74(d, tifluoroacetate J = 2.1 Hz, 1 H); 8.46 (d, J = 9.2 Hz, 1 H); 8.16(d, J = 9.9 Hz, 1 H); 7.95 (dd, J = 8.0, 2.1 Hz, 1 H); 7.53 (d, J = 8.0Hz, 1 H); 7.35-7.21 (m, 6 H); 7.16 (d, J = 8.2 Hz, 1 H); 7.06-6.96 (m, 3H); 6.95-6.90 (m, 1 H); 6.61 (dd, J = 9.9, 2.0 Hz, 1 H); 6.18 (s, 1 H);5.86-5.82 (m, 1 H); 5.44 (d, J = 9.5 Hz, 1 H); 5.16 (s, 2 H); 4.89-4.84(m, 1 H); 4.43 (s, 2 H); 3.72-3.59 (m, 1 H); 3.27-3.07 (m, 6 H); 2.24(s, 1 H); 2.07-1.69 (m, 5 H). 61 C (DMSO-d₆): δ 10.50 (d, J = 12.8 Hz, 2Di- H); 9.58 (s, 1 H); 8.81 (s, 2 H); 8.68 (d, trifluoroacetate J = 4.9Hz, 1 H); 8.45 (d, J = 9.1 Hz, 1 H); 8.08-7.98 (m, 1 H); 7.57 (dd, J =7.6, 5.3 Hz, 1 H); 7.43 (d, J = 7.7 Hz, 1 H); 7.33-7.20 (m, 4 H); 7.17(s, 1 H); 7.14 (d, J = 8.2 Hz, 1 H); 7.10-6.94 (m, 3 H); 6.91 (dd, J =8.2, 2.4 Hz, 1 H); 6.58 (d, J = 9.9 Hz, 1 H); 6.20 (s, 1 H); 5.86-5.82(m, 1 H); 5.37-5.31 (m, 1 H); 5.08 (s, 2 H); 4.89-4.84 (m, 1 H);4.33-4.15 (m, 2 H); 3.84 (s, 3 H); 3.71-3.60 (m, 1 H); 3.32-2.98 (m, 8H); 2.24 (s, 1 H); 2.13-1.67 (m, 4 H). 62 C (DMSO-d₆): δ 10.50 (s, 1 H);10.23 (s, 1 Di- H); 9.63 (s, 1 H); 9.05 (s, 1 H); trifluoroacetate 8.48(d, J = 9.2 Hz, 1 H); 8.06 (d, J = 9.9 Hz, 1 H); 7.66 (d, J = 8.2 Hz, 2H); 7.47 (d, J = 8.4 Hz, 2 H); 7.36-7.17 (m, 7 H); 7.12 (d, J = 8.2 Hz,1 H); 7.05-6.95 (m, 3 H); 6.87 (dd, J = 8.3, 2.5 Hz, 1 H); 6.56 (d, J =9.9 Hz, 1 H); 6.18 (s, 1 H); 5.86-5.81 (m, 1 H); 5.32 (d, J = 9.6 Hz, 1H); 4.89-4.84 (m, 1 H); 4.69 (s, 2 H); 4.19 (s, 2 H); 3.71-3.60 (m, 1H); 3.30-2.90 (m, 7 H); 2.24 (s, 1 H); 2.10-1.70 (m, 4 H). 63 C(DMSO-d₆): δ 10.50 (m, 2 H); 9.57 (s, 1 Di- H); 8.74 (s, 2 H); 8.52-8.42(m, 1 H); trifluoroacetate 8.05 (d, J = 9.9 Hz, 1 H); 7.47 (d, J = 1.9Hz, 1 H); 7.39-7.18 (m, 8 H); 7.13 (d, J = 8.2 Hz, 1 H); 7.03-6.94 (m, 3H); 6.89-6.85 (m, 1 H); 6.57 (d, J = 9.9 Hz, 1 H); 6.18 (d, J = 3.9 Hz,1 H); 5.86-5.82 (m, 1 H); 5.36-5.28 (m, 1 H); 4.89-4.84 (m, 1 H); 4.69(s, 2 H); 4.27-4.11 (m, 2 H); 3.80 (s, 3 H); 3.71-3.60 (m, 1 H);3.31-3.05 (m, 5 H); 3.01 (s, 2 H); 2.24 (s, 1 H); 2.05 (s, 1 H);1.91-1.72 (m, 4 H). 64 C (DMSO-d₆): δ 10.50 (2 H, d, J = 14.70 Hz), Di-9.64 (1 H, s), 9.52 (1 H, s), 8.82 (2 trifluoroacetate H, s), 8.48 (1 H,d, J = 9.18 Hz), 8.09 (1 H, d, J = 9.93 Hz), 7.70 (1 H, s), 7.63 (1 H,s), 7.34-7.27 (5 H, m), 7.26-7.19 (1 H, m), 7.14 (1 H, d, J = 8.18 Hz),7.08-7.00 (2 H, m), 6.98 (1 H, d, J = 8.13 Hz), 6.93-6.89 (1 H, m), 6.59(1 H, d, J = 9.88 Hz), 6.19 (1 H, s), 5.86 (1 H, d, J = 9.07 Hz),5.36-5.31 (1 H, m), 4.89-4.84 (1 H, m), 4.79 (2 H, s), 4.21 (2 H, d, J =9.15 Hz), 3.82 (3 H, s), 3.72-3.59 (2 H, m), 3.30-2.99 (7 H, m), 2.24 (1H, s), 2.05 (1 H, s), 1.93-1.73 (3 H, m). 65 C (DMSO-d₆): 10.51 (s, 2H); 10.22 (s, 1 Di- H); 9.64 (s, 1 H); 8.73 (m, 2 H); trifluoroacetate8.48 (d, J = 9.12 Hz, 1 H); 8.06 (d, J = 9.94 Hz, 1 H); 7.45 (s, 1 H);7.38-7.17 (m, 8 H); 7.13 (d, J = 8.18 Hz, 1 H); 7.00 (dd, J = 14.55,8.56 Hz, 3 H); 6.89-6.85 (m, 1 H); 6.56 (d, J = 9.87 Hz, 1 H); 6.21 (s,1 H); 5.86-5.81 (m, 1 H); 5.33 (dd, J = 9.07, 3.46 Hz, 1 H); 4.89-4.84(m, 1 H); 4.69 (s, 2 H); 4.27-4.08 (m, 3 H); 4.03 (dd, J = 14.04, 7.02Hz, 2 H); 3.70-3.61 (m, 1 H); 3.37-2.93 (m, 6 H); 2.24 (s, 1 H); 2.05(s, 1 H); 1.93-1.70 (m, 3 H); 1.37-1.28 (m, 3 H). 66 C (DMSO-d₆): δ10.51 (s, 2 H); 9.67 (s, 1 Di- H); 8.94 (br s, 2 H); 8.46 (d, J = 9.25Hz, trifluoroactate 1 H); 8.18 (d, J = 9.95 Hz, 1 H); 7.80 (s, 1 H);7.73 (d, J = 8.06 Hz, 1 H); 7.55 (d, J = 8.00 Hz, 1 H); 7.33-7.21 (m, 6H); 7.17 (d, J = 8.19 Hz, 1 H); 7.05-6.97 (m, 3 H); 6.91 (dd, J = 8.27,2.41 Hz, 1 H); 6.59 (m, 2 H); 6.24 (s, 1 H); 5.84 (d, J = 9.09 Hz, 1 H);5.35 (d, J = 9.65 Hz, 1 H); 5.15 (s, 2 H); 4.88-4.83 (m, 1 H); 3.72-3.60(m, 1 H); 3.27-3.11 (m, 10 H); 2.23 (br s, 1 H); 2.13-1.99 (m, 1 H);1.96-1.68 (m, 3 H). 67 C (DMSO-d₆): δ 10.51 (d, J = 4.51 Hz, 2 Di- H);9.73 (s, 1 H); 8.91 (br s, 2 H); trifluoroactate 8.46 (d, J = 9.22 Hz, 1H); 8.18 (d, J = 9.94 Hz, 1 H); 7.55 (s, 1 H); 7.39 (s, 2 H); 7.33-7.19(m, 6 H); 7.17 (d, J = 8.19 Hz, 1 H); 7.02-6.95 (m, 3 H); 6.89 (dd, J =8.25, 2.42 Hz, 1 H); 6.63-6.53 (m, 2 H); 6.23 (s, 1 H); 5.83 (d, J =9.08 Hz, 1 H); 5.35 (d, J = 9.58 Hz, 1 H); 5.06 (s, 2 H); 4.89-4.84 (m,1 H); 3.71-3.60 (m, 1 H); 3.25-3.06 (m, 10 H); 2.23 (s, 1 H); 2.05 (s, 1H); 1.96-1.68 (m, 3 H). 68 C (DMSO-d₆): δ 10.52 (d, J = 8.35 Hz, 2 Di-H); 9.78 (s, 1 H); 8.85 (s, 1 H); 8.79 (s, trifluoroactate 1 H); 8.46(d, J = 9.24 Hz, 1 H); 8.17 (d, J = 9.94 Hz, 1 H); 7.39-7.21 (m, 6 H);7.17 (d, J = 8.63 Hz, 1 H); 7.11 (s, 1 H); 7.07 (d, J = 8.05 Hz, 1 H);7.05-6.95 (m, 3 H); 6.91 (d, J = 8.29 Hz, 1 H); 6.58 (d, J = 10.06 Hz, 2H); 6.23 (s, 1 H); 5.84 (d, J = 9.07 Hz, 1 H); 5.35 (d, J = 9.56 Hz, 1H); 5.02 (s, 2 H); 4.89-4.84 (m, 1 H); 3.71-3.60 (m, 1 H); 3.28-3.05 (m,9 H); 3.04-2.87 (m, 2 H); 2.30 (s, 3 H); 2.23 (s, 1 H); 2.13-1.98 (m, 1H); 1.97-1.54 (m, 3 H).

Biological Characterization Example 9 M3 Receptor Radioligand BindingAssay

Human M3 receptor membranes (15 ug/well) from Perkin Elmer wereincubated with 0.52 nM Scopolamine Methyl Chloride, [N-methyl-3H] withor without test compounds, or a saturating concentration of Atropine (5μM) for the determination of non-specific binding. The assay was carriedout in 96-well polypropylene plates in a volume of 250 ul. The assaybuffer used was 50 mM Tris-HCl, 154 mM NaCl (pH 7.4). The final assayconcentration of DMSO was 0.5% (v/v). The plates were sealed andincubated for 2 hours at RT on an orbital shaker (slow speed). Membraneswere harvested onto 96-well unifilter GF/C filter plates pre-treatedwith 0.5% polyethyleneimine (v/v), using a filter manifold, washed fourtimes with 200 ul of assay buffer. The plates were dried before additionof 50 μl of microscint-0, sealed then read in a Trilux Microbetascintillation counter. IC50 values are determined from competitioncurves using a non-linear curve fitting program. Ki values werecalculated from IC50 values by the Cheng and Prusoff equation.

The Ki values of the most of the compounds of the examples are less than10 nM.

Example 10 β2 Adrenoceptor Radioligand Binding Assay

Human β₂ adrenoceptor membranes (7.5 ug/well) from Perkin Elmer wereincubated with 0.3 nM 125-I Cyanopindolol with or without testcompounds, or a saturating concentration of s-propranolol (2 μM) for thedetermination of non-specific binding. The assay was carried out in96-well polypropylene plates in a volume of 200 ul. The assay bufferused was 25 mM HEPES, 0.5% BSA (w/v), 1 mM EDTA, 0.02% ascorbic acid(v/v), (pH 7.4). The final assay concentration of DMSO was 0.5% (v/v).The plates were sealed and incubated for 1 hOUR at RT on an orbitalshaker (slow speed). Membranes were harvested onto 96-well unifilterGF/C filter plates pre-treated with 0.5% polyethyleneimine (v/v), usinga filter manifold, washed six times with 200 ul of wash buffercontaining 10 mM HEPES and 500 mM NaCl. The plates were dried beforeaddition of 50 μl of microscint-0, sealed then read in a TriluxMicrobeta scintillation counter. IC50 values are determined fromcompetition curves using a non-linear curve fitting program. Ki valueswere calculated from IC50 values by the Cheng and Prusoff equation.

The Ki values of the most of the compounds of the examples are less than10 nM.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

The invention claimed is:
 1. A compound which is selected from the groupconsisting of:2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-2-methylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoate;2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;2-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-2-methoxyphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoate;2-(2-bromo-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;2-(2-chloro-3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)4aphthalene-1-yl)oxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoate;2-(3-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)-methyl)benzoate;2-(3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-2,6-dimethylphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoate;2-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)-6-methoxyphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)-carbonyl)amino)methyl)phenoxy)methyl)benzoate;2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-3-methoxyphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoate;2-(2-bromo-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)-5-methoxyphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)-carbonyl)amino)methyl)phenoxy)methyl)benzoate;2-(2,6-dichloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)-phenoxy)methyl)benzoate;2-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)phenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-2,6-dimethoxyphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)-methyl)benzoate;2-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)-5-methoxyphenoxy)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)-carbonyl)amino)methyl)phenoxy)methyl)benzoate;4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-ethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;2-fluoro-4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)ethyl)benzyl4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-ethyl)-3-methoxybenzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;3-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-ethyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;(6-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)pyridin-3-yl)methyl4-((3-(S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)furan-2-yl)methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)benzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-2-methoxybenzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)furan-2-yl)methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)thiophen-2-yl)methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)thiophen-3-yl)methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)benzyl3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-3-methoxybenzyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)thiazol-2-yl)methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)isoxazol-3-yl)methyl4((3((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-1-methyl-1H-pyrazol-3-yl)methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)-carbonyl)amino)methyl)phenoxy)-methyl)benzoate;3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)phenyl)propyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)phenethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoate;(1-(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-propyl)-1H-pyrazol-4-yl)methyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoate;2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)-1H-pyrazol-1-yl)ethyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoate;4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl1-methyl-5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)-1H-pyrazole-3-carboxylate;4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-thiophene-2-carboxylate;4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl5-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-nicotinate;(R)-quinuclidin-3-yl((S)-(3-((3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)-phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3((3-(ethyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)-phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-((3-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((5-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)furan-2-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((5-(ethyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)furan-2-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)oxazol-2-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4((4(4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)thiazol-2-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)benzyl)oxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((5-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)furan-3-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-3-((S)-(3-((5-((4-((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)butoxy)carbonyl)furan-2-yl)methoxy)phenyl)(phenyl)methylcarbamoyloxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octanechloride hydrochloride;(R)-quinuclidin-3-yl((S)-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)carbamoyl)-benzyl)oxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzyl)carbamoyl)benzyl)oxy)-phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((5-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)carbamoyl)-1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((5-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)carbamoyl)-1-ethyl-1H-pyrazol-3-yl)methoxy)phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)(methyl)carbamoyl)benzyl)oxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-(ethyl(4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)benzyl)oxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)carbamoyl)-benzyl)oxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-(ethyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)-phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-(2-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)(methyl)amino)-2-oxoethyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-(2-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)amino)-2-oxoethyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((5′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3′-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-4′-methoxy-[1,1′-biphenyl]-4-yl)methoxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)furan-2-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((6-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)pyridin-3-yl)methoxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzyl)oxy)phenyl)(phenyl)-methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)amino)-2-oxoethoxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxyphenyl)amino)-2-oxoethoxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-(2-((2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-2-oxoethoxy)-phenyl)(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-(2-((3-ethoxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)amino)-2-oxoethoxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)-3-(trifluoromethyl)benzyl)oxy)phenyl)-(phenyl)methyl)carbamate;(R)-quinuclidin-3-yl((S)-(3-((3-chloro-4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate;and(R)-quinuclidin-3-yl((S)-(3-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)-2-methylbenzyl)oxy)phenyl)(phenyl)-methyl)carbamate,or a pharmaceutically acceptable salt of said compound.
 2. Apharmaceutical composition, comprising a compound or pharmaceuticallyacceptable salt according to claim 1 and one or more pharmaceuticallyacceptable carriers and/or excipients.
 3. A method for the treatment ofa broncho-obstructive or inflammatory disease, comprising administeringan effective amount of a compound or pharmaceutically acceptable saltaccording to claim 1 to a subject in need thereof, wherein saidbroncho-obstructive or inflammatory disease is asthma, chronicbronchitis, or chronic obstructive pulmonary disease.
 4. A methodaccording to claim 3, wherein said broncho-obstructive or inflammatorydisease is asthma.
 5. A combination, comprising a compound orpharmaceutically acceptable salt according to claim 1 and one or moreactive ingredients selected from the group consisting of abeta2-agonist, antimuscarinic agent, mitogen-activated protein kinase(P38 MAP kinase) inhibitor, nuclear factor kappa-B kinase subunit beta(IKK2) inhibitor, human neutrophil elastase (HNE) inhibitor,phosphodiesterase 4 (PDE4) inhibitor, leukotriene modulator,non-steroidal anti-inflammatory agent (NSAID), antitussive agent, mucusregulator, mucolytic, expectorant/mucokinetic modulator, peptidemucolytic, antibiotic, inhibitor of JAK, SYK inhibitor, inhibitor ofPI3Kdelta or PI3Kgamma, corticosteroid, and M3-antagonist/PDE4-inhibitor(MAPI).
 6. A pharmaceutical composition according to claim 2, which isin a form suitable to be administered by inhalation.
 7. A pharmaceuticalcomposition according to claim 2, which is an inhalable powder, apropellant-containing metering aerosol, or a propellant-free inhalableformulation.
 8. A device comprising, a pharmaceutical compositionaccording to claim 6, which is a single- or multi-dose dry powderinhaler, a metered dose inhaler, or a soft mist nebulizer.
 9. A methodaccording to claim 3, wherein said broncho-obstructive or inflammatorydisease is chronic bronchitis.
 10. A method according to claim 3,wherein said broncho-obstructive or inflammatory disease is chronicobstructive pulmonary disease.